CN117903097A - Recovery method of tergolian key intermediate mother liquor - Google Patents

Abstract

The invention discloses a method for recycling a key intermediate mother liquor of tergolian praecox, and belongs to the field of recycling. The recovery method comprises the following steps: (1) Dissolving tergolian key intermediate mother liquor with an organic solvent; (2) Oxidizing under the condition of an oxidant to obtain an oxide; (3) And (3) purifying the oxide to obtain a recovered product. The recovery method provided by the invention realizes the recycling of the mother liquor in the production process of the key intermediate of tergolian prazan, and reduces the economic loss caused by low crystallization yield. The recovery method of the tergolian prazan key intermediate mother liquor provided by the invention is simple, the purification purity is high, and the product yield is high.

Description

Recovery method of tergolian key intermediate mother liquor

Technical Field

The invention relates to the field of recycling, in particular to a method for recycling tergolian key intermediate mother liquor.

Background

Tergolian (TEGOPRAZAN) is also known as tegorason and is mainly used for treating gastroesophageal reflux disease and erosive esophagitis. The structural formula is as follows:

The company of pyroxene discloses a route for the synthesis of tergora using the key intermediate (4R) -5, 7-difluoro-3, 4-dihydro-2H-1-benzopyran-4-ol, as shown in formula i:

chinese patent No. 107849003A discloses a preparation method of a compound shown in a formula I, namely, 5, 7-difluoro chroman-4-ketone is used as a raw material and is reduced by using a chiral ruthenium catalyst, wherein the yield of the obtained compound shown in the formula I is 91%, and the chiral purity is 100% ee. The method involves commercializing ruthenium reagents that are difficult to purchase and are expensive.

Chinese patent No. CN115029397a discloses the use of ketoreductase to prepare compounds of formula i, but does not specifically disclose the sequence number of the enzyme. Chinese patent No. 101341149B discloses a preparation method of a compound of formula I, namely, adding tetrahydrofuran solution of 5, 7-difluoro chroman-4-one into mixed solution consisting of chiral reagent (S) -1-methyl-3, 3-diphenyl-1H, 3H-pyrrolo [1,2-c ] [1,3,2] oxazaborolidine, borane-dimethyl sulfide complex and tetrahydrofuran, purifying by column chromatography after the reaction is finished, wherein the chiral purity is 86% ee, and recrystallizing by hexane to obtain the compound of formula I, wherein the optical purity is more than 99% ee, and the yield is 58%. The method has low yield and low economic benefit.

The preparation process of the compound shown in the formula I is optimized by Chinese patent No. 112851646A, chiral purity is controlled by slowly dripping tetrahydrofuran solution of 5, 7-difluoro chroman-4-ketone, column chromatography purification is not needed in post-treatment, and ethyl acetate/n-hexane is directly used for recrystallization to obtain the compound shown in the formula I with optical purity of more than 99% ee, and the yield is 66%. Although the yield of the method is improved to a certain extent, the yield is still lower and the crystallization loss is large.

In view of the fact that the yield is low after the compound shown in the formula I is crystallized and purified in the prior art, the residual mother liquor material also contains more than 90 weight percent of 5, 7-difluoro-3, 4-dihydro-2H-1-benzopyran-4-ol, the chiral purity is low, and the mother liquor material cannot be recycled, so that the overall cost is high. Therefore, a method for recovering the mother liquor is developed, and the method has great significance for synthesis of tergolian prazan.

Disclosure of Invention

Aiming at the problems existing in the prior art, the invention provides a method for recycling the key intermediate mother liquor of tergorlazan, and the obtained recycled product has high purity and high yield, and the synthetic cost of tergorlazan is effectively reduced.

In order to solve the technical problems, the invention adopts the following technical scheme:

a method for recovering a key intermediate mother liquor of tergorlazan, wherein the key intermediate mother liquor of tergorlazan contains a compound with a structure of a formula II, the recovered product has a structure of a formula III,

The recovery method is that the tergolian key intermediate mother liquor material and the oxidant are subjected to oxidation reaction to obtain an oxidation product, and then the oxidation product is purified to obtain a recovery product.

Preferably, the oxidation reaction has the following reaction formula:

Preferably, the recovery method comprises the steps of:

(1) Dissolving key intermediate mother liquor of tergorlazan by using an organic solvent to obtain mother liquor solution;

(2) Adding an oxidant into the mother liquor stock solution for oxidation reaction to obtain an oxidation product;

(3) Purifying the oxidized product to obtain a recovered product.

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

still more preferably, the organic solvent is methylene chloride.

Further preferably, in the step (1), the ratio of the organic solvent to the mother liquor is 5-10 mL/1 g.

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

Still more preferably, the oxidizing agent is sodium hypochlorite.

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

Further preferably, in the step (2), the temperature of the oxidation reaction is 0 to 30 ℃ and the reaction time is 1 to 4 hours.

Further preferably, in step (2), the purification process of the oxidation product is recrystallisation.

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

Still more preferably, in the solvent for recrystallization, the volume ratio of the good solvent to the poor solvent is 1:5-20.

Further preferably, the tergolian key intermediate mother liquor is a mother liquor produced by preparing the tergolian key intermediate compound of formula I,

Still more preferably, the compound of formula I is prepared as follows:

Still more preferably, the preparation process of the tergolian key intermediate mother liquor comprises the following steps:

Reacting 5, 7-difluoro chroman-4-one with S-Me-CBS and borane dimethyl sulfide complex, recrystallizing and purifying the obtained reactant to obtain a compound of a formula I, wherein the residual recrystallization liquid is a compound mother liquor of the formula I, and decompressing the compound mother liquor of the formula I to remove the solvent to obtain the tergolian key intermediate mother liquor.

Preferably, the tergolian key intermediate mother liquor contains more than 90 weight percent of 5, 7-difluoro-3, 4-dihydro-2H-1-benzopyran-4-ol, wherein the R configuration accounts for 60-70 percent and the S configuration accounts for 30-40 percent.

Compared with the prior art, the invention has the following beneficial effects:

The method provided by the invention realizes the recycling of the mother liquor material in the production process of the key intermediate of tergolian praecox, and reduces the economic loss caused by low crystallization yield. The recovery method disclosed by the invention is simple to operate, the used reagents are all common reagents, the purification purity is high, the product yield is high, and the production cost of the key tergolian intermediate is greatly reduced.

Drawings

FIG. 1 is a chiral purity profile of the compound of formula I prepared in example 1.

FIG. 2 is a chiral purity profile of a mother liquor of a compound of formula I prepared in example 2.

FIG. 3 is a chart showing the liquid phase purity of the mother liquor of the compound of formula I prepared in example 2.

FIG. 4 is a liquid phase purity profile of the compound of formula III prepared in example 6.

FIG. 5 is a liquid phase purity profile of the compound of formula III prepared in comparative example 1.

Detailed Description

The following non-limiting examples will enable those of ordinary skill in the art to more fully understand the invention and are not intended to limit the invention in any way. The following is merely exemplary of the scope of the invention as it is claimed and many variations and modifications of the invention will be apparent to those skilled in the art in light of the disclosure, which should be considered as falling within the scope of the invention as claimed.

Where numerical ranges are provided in the examples, it is understood that unless otherwise stated herein, both endpoints of each numerical range and any number between the two endpoints are significant both in the numerical range. Unless defined otherwise, 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.

The application is further illustrated by means of the following specific examples. The experimental methods in the following examples are conventional methods unless otherwise specified. The various chemical reagents used in the examples of the present application were obtained by conventional commercial means unless otherwise specified. Wherein 3, 5-difluorophenol, sulfuric acid, methylene dichloride, sodium hypochlorite, sodium bicarbonate and TEMPO used in the specific embodiment of the application are all owned products of a company; acrylonitrile, copper hydroxide were purchased from Ann Ji reagent.

In the following examples, the operations of stirring, reflux reaction, temperature control, etc. were carried out using instruments conventionally used in the art: the manufacturers of the electronic constant-speed stirrer, the lifting numerical control constant-temperature bath, the circulating water type vacuum pump, the low-temperature precise constant-temperature circulating tank and other instruments are former name of a region in eastern zhejiang Xin Li instruments company; in the following examples, the manufacturer of the purity measuring instrument for products is Agilent corporation.

In the examples below, yield = actual weight/theoretical weight x 100%;

purity was measured using High Performance Liquid Chromatography (HPLC).

Example 1

Preparation of Compounds of formula I

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

Synthesis of formula I-1:

to a reaction flask, (130 g,1.00 mol) of 3, 5-difluorophenol, (210 g,3.95 mol) of acrylonitrile was added, stirred and dissolved, copper hydroxide (100 g,1.03 mol) was added, the temperature was raised to 80 ℃, the reaction was refluxed for 48 hours, after the reaction was completed, cooled to room temperature, concentrated under reduced pressure, 500mL of methylene chloride and 1L of purified water were added, the mixture was stirred and separated, the organic layer was washed with 500mL of purified water, the separated layer was dried over anhydrous sodium sulfate, filtered, and the organic layer was concentrated under reduced pressure to remove the organic solvent, to give the compound of formula I-1 (110 g, 60%).

Synthesis of compounds of formula III:

Adding the (110 g) formula I-1 obtained in the last step into a glass reaction bottle filled with 300g of concentrated sulfuric acid, heating to 50 ℃, preserving heat, reacting, completely dropwise adding precooled 1L of pure water into the reaction, adding 1.1L of dichloromethane, stirring for dissolving, adjusting pH to 7 with 5% of sodium bicarbonate solution, layering, removing the organic solvent from the organic phase under reduced pressure, adding 550mL of n-heptane, stirring, filtering, and drying a filter cake at 40 ℃ to obtain the compound (90 g, 80%) of the formula III.

Synthesis of a compound of formula I:

A3L three-necked flask was charged with anhydrous THF (660 mL) and S-Me-CBS (1 mol/L in toluene, 90mL,90 mmol) and the borane dimethyl sulfide complex (10 mol/L,99mL,990 mmol) was injected at room temperature under argon. 5, 7-difluoro-chroman-4-one (166 g,900 mmol) was dissolved in anhydrous tetrahydrofuran (1660 mL) and slowly added dropwise to the system over a period of 5.5 hours. After the dripping, the mixture is left overnight. Slowly pouring the reaction solution into ice-water bath cooled methanol to generate a large amount of bubbles, stirring until no obvious bubbles are generated, and concentrating to remove the solvent. 1000mL of ethyl acetate was added to dissolve, and the organic phase was washed with water (500 mL, 300 mL) and 10% brine (200 mL) in this order, dried over anhydrous sodium sulfate, filtered, concentrated to an oil, and left to stand as a yellow solid at room temperature. Chiral purity was 93.6% ee (OZ-H column, n-hexane/isopropanol=95/5, flow rate=1 mL/min, detection wavelength 220 nm) by chiral HPLC. The above solid was dissolved in a mixed solvent composed of n-hexane and ethyl acetate (n-hexane/ethyl acetate=17:1) by heating, and recrystallized to obtain 111g of needle-like crystals with a yield of 66.5%. Chiral purity was >99.9% ee as measured by chiral HPLC, and chiral purity profile is shown in figure 1. The remaining liquid is a mother liquor of compound I (formula I).

Example 2

Taking a compound I (formula I) mother liquor (example 1), decompressing and desolventizing to obtain a compound I mother liquor (tergorlazan key intermediate mother liquor), detecting by HPLC, wherein the purity of the mother liquor is 94%, the chiral purity is less than 40% ee, the chiral purity map of the compound I mother liquor is shown in figure 2, and the liquid phase purity map is shown in figure 3.

A mother liquor of the compound I (10 g,50 mmol), 100g of DCM,4.2g of 50mmol of sodium bicarbonate, 78mg of 0.5mmol of TEMPO,1.1g of 10mmol of sodium bromide, 10g of drinking water, cooling to 0 ℃, dropwise adding 48g of sodium hypochlorite solution (10% concentration, 64.8 mmol) to the solution, keeping the reaction at a constant temperature, dropwise adding 10% of sodium thiosulfate solution (128 g) to quench the reaction after the reaction is complete, layering, extracting the aqueous phase with 50g of dichloromethane, combining two organic phases, drying the organic phases with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain a residue, heating and dissolving the residue with 60g of methanol aqueous solution (10 g of methanol+50 g of water), cooling to 10 ℃, filtering, drying at 40 ℃ to obtain 8.5g of the compound III (compound of the formula III) with a yield of 85.9% and purity of 99.5%.

Examples 3 to 8

Referring to example 2, sodium hypochlorite was used as the oxidant, except that the solvent system for recrystallization during purification was different, the volume ratio of good solvent to poor solvent was 1:5, and the purification results were as follows:

Examples	Purifying the recrystallized solvent	Purity of	Yield is good
				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％

Conclusion: the isopropyl acetate/petroleum ether system is used for crystallization, so that the yield is highest, and the impurity removal effect is best. The liquid phase purity profile of compound III (compound of formula III) prepared in example 6 is shown in FIG. 4.

Example 9

A mother liquor of compound I (10 g,50 mmol), 100gDCM, (4.2 g,50 mmol) sodium bicarbonate, (78 mg,0.5 mmol) TEMPO, (1.1 g,10 mmol) sodium bromide, 10g drinking water, cooling to 0 ℃, dropwise adding 46g calcium hypochlorite solution (10% strength, 32.4 mmol), keeping the temperature for reaction, after completion of the reaction, dropwise adding 10% sodium thiosulfate solution (128 g) for quenching the reaction, layering, extracting the aqueous phase with 50g methylene chloride, combining the two organic phases, drying the organic phases with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain a residue, recrystallizing the residue with 10g isopropyl acetate and 50g petroleum ether, filtering, drying at 40 ℃ to obtain 9.0g of compound III (compound of formula III) with a yield of 89.0% and a purity of 99.7%.

Example 10

To a 250mL three-necked flask under the protection of nitrogen gas, mother liquor (10 g,50 mmol) of the compound I, 100g of methylene chloride, 10g of 3A molecular sieve, PCC (17.5 g,81 mmol) are sequentially added, the reaction is completed after stirring and room temperature reaction for 3 hours, filtration is carried out, 50g of methylene chloride is used for leaching filter cakes, the residue is obtained after decompression concentration, 10g of isopropyl acetate and 50g of petroleum ether are used for recrystallization, filtration and drying at 40 ℃ are carried out, 8.4g of the compound III (compound of formula III) is obtained, the yield is 84.9%, and the purity is 98.5%.

Example 11

A250 mL three-necked flask was charged with a mother liquor of Compound I (10 g,50 mmol), 100g of methylene chloride, 10g of silica gel, PDC (24.8 g of 81 mmol) in this order under nitrogen protection, stirred, reacted at room temperature for 3 hours, filtered, and the filter cake was rinsed with 50g of methylene chloride, and concentrated under reduced pressure to give a residue, which was recrystallized from 10g of isopropyl acetate and 50g of petroleum ether, filtered, and dried at 40℃to give 8.0g of Compound III (Compound of formula III) in 80.9% yield and 99.0% purity.

Comparative example 1

To a 250mL three-necked flask, mother liquor (10 g,50 mmol) of the compound I, 100g of dichloromethane, 0.1g of sodium tungstate, 13.7g of 30% hydrogen peroxide slowly and dropwise, reacting at room temperature for 3 hours, completely reacting, dropwise adding an aqueous solution of sodium sulfate, quenching, layering, extracting a water layer with 50g of dichloromethane, concentrating an organic layer under reduced pressure to obtain a residue, recrystallizing the residue with 10g of isopropyl acetate and 50g of petroleum ether, filtering, drying at 40 ℃ to obtain 5.6g of compound III (compound of formula III), wherein the yield is 56.6%, and the purity is 95.8%. The liquid phase purity profile of compound III (compound of formula III) prepared in comparative example 1 is shown in FIG. 5.

Finally, it should be noted that the above description is only for illustrating the technical solution of the present invention, and not for limiting the scope of the present invention, and that the simple modification and equivalent substitution of the technical solution of the present invention can be made by those skilled in the art without departing from the spirit and scope of the technical solution of the present invention.

Claims (10)

1. A method for recycling tergorlazan key intermediate mother liquor is characterized in that tergorzan key intermediate mother liquor and an oxidant are subjected to oxidation reaction to obtain an oxidation product, and then the oxidation product is purified to obtain a recovered product;

the tergolian key intermediate mother liquor contains a compound with a structure of a formula II, the recovered product has a structure of a formula III,

2. The recycling method according to claim 1, comprising the steps of:

(1) Dissolving key intermediate mother liquor of tergorlazan by using an organic solvent to obtain mother liquor solution;

(2) Adding an oxidant into the mother liquor stock solution for oxidation reaction to obtain an oxidation product;

(3) Purifying the oxidized product to obtain a recovered product.

3. The recovery method according to claim 2, wherein in step (1), the organic solvent is selected from at least one of dichloromethane, chloroform, acetonitrile; the organic solvent is preferably methylene chloride; the ratio of the organic solvent to the mother liquor is 5-10mL:1g.

4. The recovery method according to claim 2, wherein in step (2), the oxidizing agent is selected from at least one of sodium hypochlorite, calcium hypochlorite, PDC, PCC; sodium hypochlorite is preferred.

5. The recovery process of claim 2, wherein in step (2), the molar ratio of the oxidizing agent to the compound of formula II in the mother liquor is from 1.2 to 3.0:1.0.

6. The recovery method according to claim 2, wherein in the step (2), the temperature of the oxidation reaction is 0 to 30 ℃ and the reaction time is 1 to 4 hours.

7. The recovery method according to claim 2, wherein in the step (2), the purification method of the oxidized product is a recrystallization, and the recrystallized solvent is at least one solvent selected from the group consisting of methanol/water, ethanol/water, isopropyl alcohol/water, ethyl acetate/petroleum ether, isopropyl acetate/petroleum ether, methylene chloride/petroleum ether, toluene/petroleum ether; in the recrystallized solvent, the volume ratio of the good solvent to the poor solvent is 1:5-20.

8. The recovery method according to claim 1 or 2, wherein the tergolian key intermediate mother liquor is a mother liquor produced in the preparation of a tergolian key intermediate compound of formula I, wherein the compound of formula I has the following structure:

9. the recovery process of claim 8, wherein the compound of formula I is prepared as follows:

10. The recovery method according to claim 8, wherein the process for preparing the tergolian key intermediate mother liquor comprises the steps of:

Reacting 5, 7-difluoro chroman-4-one with S-Me-CBS and borane dimethyl sulfide complex, recrystallizing and purifying the obtained reactant to obtain a compound of a formula I, taking the recrystallized residual liquid as a compound I mother solution, and decompressing the compound I mother solution to remove the solvent to obtain the tergore prazane key intermediate mother solution.