CN112661736B - Synthetic method of tylosin intermediate - Google Patents
Synthetic method of tylosin intermediate Download PDFInfo
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Abstract
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a synthetic method of a tylosin intermediate, which comprises the following steps: the preparation method comprises the steps of preparing iodo-acetate by taking a compound A as a raw material through primary hydroxyl iodination and acetylation, reducing iodide into a methyl compound, preparing a benzyl protection product, removing methyl protection, and performing swern hydroxyl oxidation for five-step reaction to obtain a tylagliflozin intermediate, namely a compound F. The invention avoids the explosive danger caused by that three secondary alcohols are protected by NaH due to the adoption of selective silicon-based protection primary alcohol in the prior art, further simplifies the reaction steps, can obtain a final product with high yield without column chromatography, and has the total yield of 56 percent. The method provided by the invention has no high-low temperature reaction and dangerous reagents, the used raw materials are easy to obtain, the cost is greatly saved, the cost is only 1/2-1/3 of the currently reported route, and the method has obvious advantages.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a synthetic method of a tylosin intermediate.
Background
Diabetes mellitus is a metabolic disease which is characterized by hyperglycemia due to insulin secretion defect or insulin dysfunction, the prior art also shows that the kidney plays an important role in regulating blood sugar, a substance responsible for sugar resorption in renal tubule sugar is 'sodium-glucose cotransporter 2' (SGLT-2), and an SGLT-2 inhibitor can selectively inhibit SGLT-2, so that the effects of reducing body weight, rarely causing hypoglycemia, having a treatment effect independent of a hypoglycemic pathway of insulin secretion and the like are achieved. SGLT-2 inhibitors include tylosin, dapagliflozin, regagliflozin and the like, wherein tylosin is the strongest SGLT-2 inhibitor found at present, and provides a new choice for clinical treatment.
In the process of synthesizing the tylosin, a large amount of tylosin intermediates are inevitably needed for medicine synthesis, the intermediate is named as (3R,4S,5R,6R) -3,4,5-tri (benzyloxy) -tetrahydro-6-methyl pyran-2-one in Chinese and named as (3R,4S,5R,6R) -3,4,5-tris (benzyloxy) -6-methyl trahydro-2H-pyran-2-one in English, the intermediate is used as a raw material for entering GMP production of the tylosin, the demand of the intermediate is very large, the required purity is high, the single impurity is low, and the intermediate is quick, low in cost and high in efficiency, and the large amount of the tylosin intermediates are the key for controlling the purity of the tylosin and reducing the cost.
Tiagliflozin intermediate
The synthetic method has the advantages that firstly, the synthetic method is too long in path, seven steps of reaction are needed, a large amount of benzyl ether is generated in the synthetic process, and qualified target products can be obtained only through column chromatography; secondly, the synthesis method uses a system of NaH and DMF, resulting in the generation of a large amount of hydrogen, which is calculated from 1kg of starting material, requiring 1kg of NaH to generate 12.6mol of H in total of 283L2Is extremely easy to explode, brings great risk to the smooth proceeding of the reaction, and is difficult to produce in large quantities; in addition, the method uses lithium aluminum hydride in the synthesis process, the reaction water content needs to be strictly controlled, the processing is difficult and is not suitable for mass production, finally, the increase of the synthesis steps causes the final yield to be obviously lower, and the relatively expensive reagents and the strict reaction conditions further limit the large-scale application of the method.
Existing synthetic route of tylosin intermediate
Disclosure of Invention
In view of the defects of the prior art, the invention aims to provide a synthetic method of a tylosin intermediate, which simplifies reaction steps, can obtain a high-yield final product through crystallization without column chromatography, has a total yield of 56 percent, remarkably improves the synthesis efficiency, and simultaneously avoids the danger that benzyl protection three secondary alcohols are easy to explode because only NaH is adopted due to the adoption of selective silicon-based protection primary alcohol in the prior art.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a method for synthesizing a tylosin intermediate, the method comprising the steps of:
s1: taking a compound A as a raw material, performing iodination on primary hydroxyl, performing acetylation reaction on acetic anhydride/triethylamine to obtain a pretreated product, and performing aftertreatment to obtain a compound B;
s2: carrying out reduction reaction on the compound B to obtain a compound C;
s3: removing acetyl protection from the compound C through catalytic amount of sodium methoxide, performing benzyl protection on a NaOH/BnBr system to obtain a pre-treated product, and performing post-treatment to obtain a compound D;
s4: heating and hydrolyzing the compound D through a sulfuric acid solution, an acetic acid solution and 1, 4-dioxane to obtain a pretreated product, and performing aftertreatment to obtain a compound E;
s5: performing swern oxidation reaction on the compound E to obtain a crude product of a compound F;
s6: and (4) adding the crude product of the compound F obtained in the step S5 into ethanol, heating until the mixture is refluxed and dissolved, cooling for crystallization, and performing suction filtration to obtain a purified compound F, wherein the reaction formula is shown as follows:
further, the raw materials used in the step S1 for preparing the compound B from the compound a include the compound a, triphenylphosphine, imidazole, tetrahydrofuran and iodine, the mass ratio of the compound a to the triphenylphosphine to the imidazole is 1.8-2.3:3:1, and the mass of the iodine is 1.2-1.6 times that of the compound a.
Further, the post-processing of step S1 is: cooling a product obtained after primary hydroxyl iodo and acetic anhydride/triethylamine acetylation reaction to 25-30 ℃, adding ethyl acetate and 10% by mass of sodium chloride aqueous solution, stirring for 10min, separating liquid, washing an organic phase for 1 time by using the 10% by mass of sodium chloride aqueous solution, wherein the sodium chloride aqueous solution contains 30-50% by volume of concentrated hydrochloric acid, washing the organic phase for 1 time by using the aqueous solution containing sodium thiosulfate pentahydrate and sodium chloride, concentrating to remove an organic solvent, adding isopropanol, performing suction filtration, washing a filter cake by using the isopropanol, and drying to obtain a compound B.
Further, in the step of preparing the compound C by the reduction reaction of the compound B in the step S2, the compound B prepared in the step S1, the palladium-carbon catalyst, the diisopropylethylamine and the methanol are added into a reaction bottle, and H is introduced into the reaction bottle2The displacement reaction is carried out for 3 times;
or the reduction reaction can also be that the compound B prepared in the step S1, water and zinc powder are added into a reaction bottle, acetic acid is dripped into the reaction bottle to react completely, the mixture is filtered, a filter cake is washed by ethyl acetate, a filtrate is extracted by ethyl acetate for 1 time, an ethyl acetate phase is washed by water for 1 time, saturated sodium bicarbonate is washed by 1 time, saturated saline is washed by 1 time, the mixture is concentrated and dried, a solid is pulped by methanol, the filtration is carried out, and a filter cake is dried to obtain a white solid C so as to prepare the compound C.
Further, in the step S3, the mass ratio of sodium methoxide used for deacetylation protection of the compound C by catalytic amount of sodium methoxide to the compound C is 1: 50-55.
Further, the post-processing of step S3 includes: and (3) cooling the product pretreated in the step (S3) to 25-30 ℃, adding ethyl acetate and water with the temperature of 10-15 ℃, separating liquid, extracting the water phase for 1 time by using ethyl acetate, combining organic phases, washing for 1 time by using hydrochloric acid, washing for 1 time by using saturated saline solution, concentrating and drying, adding 1, 4-dioxane into the obtained concentrate, concentrating and drying again to obtain the compound D.
Further, the compound D in step S4 needs to be heated to 100 ℃ for reflux reaction for 10-12h through the reaction of heating and hydrolyzing with sulfuric acid solution, acetic acid solution and 1, 4-dioxane.
Further, the post-processing of step S4 includes: and (3) cooling the product pretreated in the step S4 to 20-25 ℃, adding water and ethyl acetate, separating liquid, extracting the water phase with ethyl acetate for 2 times, combining the ethyl acetate phases, washing with water for 1 time, washing with saturated sodium bicarbonate for 1 time, washing with saturated salt solution for 1 time, concentrating and drying, adding ethanol into the obtained concentrate, concentrating and drying to obtain the compound E.
Further, the step of swern oxidation reaction in the step S5 includes: and (3) adding DMSO (dimethyl sulfoxide) into a reaction bottle, controlling the temperature to be 20-25 ℃, dropwise adding anhydride, dissolving the compound E obtained in the step S4 into the DMSO, and then dropwise adding the compound E into the reaction bottle to react at 20-25 ℃.
Compared with the prior art, the invention has the following advantages:
(1) the invention simplifies the synthetic route, the synthetic route disclosed by the prior art needs seven-step reaction, the synthetic route provided by the invention only needs five-step reaction, the reduction of the reaction steps enables the yield to be obviously improved, and experiments prove that the total yield of the method provided by the invention can reach 56 percent and the achievement is good.
(2) The invention avoids the danger that benzyl protection three secondary alcohols can only adopt NaH and is easy to explode because selective silicon base is adopted to protect primary alcohol in the prior art, adjusts the reaction route in order to avoid benzyl protection on a NaH and DMF system, firstly reduces primary alcohol iodo into methyl, eliminates the interference of protecting groups, and then adopts cheap NaOH and BnBr for protection, thereby avoiding the use of the NaH and DMF system.
(3) In the prior art, benzyl protection is carried out on a NaH and DMF system, long-time reaction of NaH and BnBr is required, so that the cost is greatly increased, particularly, a large amount of high-boiling point benzyl ether is generated in the reaction, and the intermediate and the final product are dissolved in the benzyl ether due to good solubility in the benzyl ether, so that the intermediate and the final product are further removed by column chromatography, and the trouble is brought to the synthesis operation.
(4) The method provided by the invention has simple steps, no high-low temperature reaction and no dangerous reagent, the used raw materials are easy to obtain, the method is suitable for large-scale production, the cost is only 1/2-1/3 of the currently reported route, and the method has obvious advantages and wide application prospect.
Description of the drawings:
fig. 1 is a chromatogram of the purity of the tagatosine intermediate obtained by the synthetic method of example 3.
Fig. 2 is a nuclear magnetic resonance spectrum of the intermediate of telagliflozin obtained by the synthetic method of example 3.
Detailed Description
The present invention will be further explained by way of specific embodiments in the form of examples. However, the scope of the above subject matter of the present invention is not limited to the following examples, and it should be noted that the instruments and reagents used in the present invention are commercially available known products.
Example 1 Synthesis method of a Ticagrelnet intermediate
A method of synthesizing a tylosin intermediate, the method comprising:
s1: taking a compound A as a raw material, performing primary hydroxyl iodination, performing acetylation reaction on acetic anhydride/triethylamine to obtain a pretreated product, and performing aftertreatment to obtain a compound B:
1) pretreatment: adding 52.9g of compound A, 88.2g of triphenylphosphine, 29.4g of imidazole and 300mL of tetrahydrofuran into a reaction bottle, heating to reflux, adding 63.5g of iodine into 150mL of tetrahydrofuran to dissolve, slowly dropping into the reaction bottle for 2.5h, after dropping, keeping the temperature for reaction for 0.5h, after the reaction is finished, cooling to 20 ℃, adding 146g of pyridine, quickly dropping 189g of anhydride, controlling the temperature in a 35 ℃ water bath, reacting for 12h, sampling, detecting by thin layer chromatography (a developing agent is DCM/MEOH 10/1; 2mL, adding 1 drop of acetic acid), and detecting that the compound A basically disappears to obtain a pretreated product;
2) and (3) post-treatment: cooling the pretreated product obtained in the step S1 to 25 ℃, adding 720mL of ethyl acetate and 480mL of 10% sodium chloride aqueous solution by mass fraction, stirring for 10min, separating, washing the obtained organic phase for 1 time by using 360mL of 10% sodium chloride aqueous solution by mass fraction, wherein the sodium chloride aqueous solution contains 108mL of concentrated hydrochloric acid, washing the organic phase for 1 time by using 480mL of 10% sodium chloride aqueous solution by mass fraction (containing 24g of sodium thiosulfate pentahydrate), concentrating to remove the organic solvent, adding 400mL of isopropanol, performing suction filtration, washing the filter cake by using isopropanol, and drying to obtain 85.5g of a white solid, namely a compound B;
s2: and (3) carrying out reduction reaction on the compound B to obtain a compound C:
85.5g of the compound B obtained in the step S1, 4.8g of palladium-on-carbon catalyst, 33.6g of diisopropylethylamine and 1L of methanol were put in a reaction flask, and H was introduced2Performing displacement reaction for 3 times, reacting at room temperature until compound B basically disappears by thin layer chromatography (developer EA/PE is 1/5; 2mL), filtering with diatomaceous earth, washing filter cake with methanol, concentrating and drying filtrate, pulping with 100mL methanol, filtering, and drying filter cake to obtain white solid, to obtain compound C62.5 g;
s3: removing acetyl protection from the compound C through catalytic amount of sodium methoxide, then performing benzyl protection on a NaOH/BnBr system to obtain a pre-treated product, and performing post-treatment to obtain a compound D:
1) pretreatment: adding 62.5g of the compound C obtained in the step S2, 1.3g of sodium methoxide and 400mL of anhydrous methanol into a reaction bottle, stirring for 0.5h at 25 ℃, detecting that the compound C basically disappears by thin-layer chromatography (a developing agent is DCM/MEOH 10/1; 2 mL; 1 drop of acetic acid is added), adding 0.48g of water for quenching reaction, concentrating and drying, adding 100mL of 2-methyltetrahydrofuran, reacting for 0.5h at 40 ℃, concentrating and drying again, adding the same volume of 2-methyltetrahydrofuran for 1 time to obtain a concentrate (an intermediate with three acetyl protection removed), adding the concentrate into 550mL of 2-methyltetrahydrofuran for heating and dissolving, transferring into the reaction bottle, adding 62g of sodium hydroxide and 9.6g of tetrabutylammonium iodide, heating to reflux, reacting for 0.5h, removing a stock solution in a water separator, diluting 126.6g of benzyl bromide with 300mL of 2-methyltetrahydrofuran, slowly adding into the reaction bottle, dropwise adding for 3h, reacting for 6h under constant temperature, and detecting the concentrate by thin layer chromatography (developing solvent is DCM/MEOH 10/1; 2 mL; and adding 1 drop of acetic acid) to obtain pretreated product;
2) and (3) post-treatment: cooling the pretreated product obtained in the step S3 to 25 ℃, adding 200mL of ethyl acetate and 300mL of water with the temperature of 10 ℃, separating liquid, extracting the water phase for 1 time by using 100mL of ethyl acetate, combining organic phases, washing for 1 time by using 150mL of 1mol/L hydrochloric acid, washing for 1 time by using saturated saline, concentrating and drying, adding 50mL of 1, 4-dioxane into the obtained concentrate, concentrating and drying again, and obtaining a light yellow oily substance, namely the compound D100.5 g;
s4: and (3) heating and hydrolyzing the compound D by a sulfuric acid solution, an acetic acid solution and 1, 4-dioxane, and carrying out aftertreatment to obtain a compound E:
1) pretreatment: adding 100.5g of the compound D prepared in the step S3 and a sulfuric acid solution (102g of concentrated sulfuric acid is diluted by water to 350mL), an acetic acid solution (279g of acetic acid is diluted by water to 350mL of an 80% acetic acid aqueous solution) and 460mL of 1, 4-dioxane into a reaction bottle, heating to 100 ℃, carrying out reflux reaction for 10 hours, and detecting that the compound D basically disappears by thin layer chromatography (a developing agent is EA/PE (5/1); 2mL) to obtain a pretreated product;
2) and (3) post-treatment: cooling the pretreated product obtained in the step S4 to 20 ℃, adding 1L of water and 200mL of ethyl acetate, separating liquid, extracting the water phase with 200mL of ethyl acetate for 2 times, combining the ethyl acetate phases, washing with 100mL of water for 1 time in sequence, washing with 300mL of saturated sodium bicarbonate for 1 time, washing with 200mL of saturated saline for 1 time, concentrating and drying, adding an ethanol solution into the obtained concentrate, concentrating and drying to obtain a white-like solid, namely a compound E51.1 g;
s5: and (3) carrying out a swern oxidation reaction on the compound E to obtain a crude product of the compound F:
adding 400mL of DMSO into a reaction bottle, dropwise adding 200mL of anhydride at the temperature of 20 ℃, dissolving 51.1g of the compound E obtained in the step S4 into 160mL of DMSO, dropwise adding into the reaction bottle, reacting at the temperature of 20 ℃, detecting the substantial disappearance of the compound E through thin-layer chromatography (the developing agent is EA/PE (equal to 5/1; 2 mL)), pouring the reaction liquid into 2L of ice water for quenching reaction, stirring for 0.5h, extracting for 3 times with 200mL of ethyl acetate, washing the ethyl acetate phase for 2 times with 100mL of sodium chloride aqueous solution with the mass fraction of 10%, washing for 1 time with 300mL of saturated sodium bicarbonate solution, washing for 1 time with 200mL of saturated saline, concentrating and drying to obtain a crude product of the compound F;
s6: and (4) adding the crude product of the compound F obtained in the step S5 into 200mL of ethanol, heating until the mixture is refluxed and dissolved, cooling for crystallization, and performing suction filtration to obtain 38.1g of a purified compound F.
Example 2 Synthesis method of a Ticagrelnet intermediate
A method of synthesizing a tylosin intermediate, the method comprising:
s1: taking a compound A as a raw material, performing primary hydroxyl iodination, performing acetylation reaction on acetic anhydride/triethylamine to obtain a pretreated product, and performing aftertreatment to obtain a compound B:
1) pretreatment: adding 67.6g of compound A, 94.08g of triphenylphosphine, 29.4g of imidazole and 300mL of tetrahydrofuran into a reaction bottle, heating to reflux, adding 108.2g of iodine into 150mL of tetrahydrofuran for dissolving, slowly dropping into the reaction bottle for 3.2h, keeping the temperature for reaction for 1h after dropping is finished, cooling to 25 ℃ after the reaction is finished, adding 146g of pyridine, quickly dropping 189g of anhydride, controlling the temperature in a 40 ℃ water bath, reacting for 15h, sampling, detecting by thin-layer chromatography (a developing agent is DCM/MEOH (10/1); 2 mL; and then adding 351 drop of acetic acid), and detecting that the compound A basically disappears to obtain a pretreated product;
2) and (3) post-treatment: cooling the pretreated product obtained in the step S1 to 30 ℃, adding 720mL of ethyl acetate and 480mL of 10% sodium chloride aqueous solution by mass fraction, stirring for 10min, separating, washing the obtained organic phase for 1 time by using 360mL of 10% sodium chloride aqueous solution by mass fraction, wherein the sodium chloride aqueous solution contains 180mL of concentrated hydrochloric acid, washing the organic phase for 1 time by using 480mL of 10% sodium chloride aqueous solution by mass fraction (containing 24g of sodium thiosulfate pentahydrate), concentrating to remove the organic solvent, adding 400mL of isopropanol, performing suction filtration, washing the filter cake by using isopropanol, and drying to obtain white solid, namely a compound B115 g;
s2: and (3) carrying out reduction reaction on the compound B to obtain a compound C:
adding 115g of the compound B prepared in the step S1, 0.5L of water and 24g of zinc powder into a reaction bottle, heating to 90 ℃, dropwise adding acetic acid, reacting, detecting that the compound B basically disappears by thin-layer chromatography (the developing agent is EA/PE (equal to 1/5; 2 mL)), carrying out suction filtration, washing a filter cake with a small amount of ethyl acetate, extracting the obtained filtrate once with 150mL of ethyl acetate, washing the extracted ethyl acetate phase with 100mL of water for 1 time, washing the extracted ethyl acetate phase with 100mL of saturated sodium carbonate for 1 time and washing the extracted ethyl acetate phase with 200mL of saturated salt water for 1 time, concentrating and drying, pulping the solid with 100mL of methanol, carrying out suction filtration, and drying the filter cake to obtain a white solid, thus obtaining 81.5g of the compound C;
s3: removing acetyl protection from the compound C through catalytic amount of sodium methoxide, then performing benzyl protection on a NaOH/BnBr system to obtain a pre-treated product, and performing post-treatment to obtain a compound D:
1) pretreatment: adding 81.5g of the compound C obtained in the step S2, 1.3g of sodium methoxide and 400mL of anhydrous methanol into a reaction bottle, stirring for 0.5h at 30 ℃, detecting that the compound C basically disappears by thin-layer chromatography (a developing agent is DCM/MEOH 10/1; 2 mL; 1 drop of acetic acid is added), adding 0.48g of water for quenching reaction, concentrating and drying, adding 100mL of 2-methyltetrahydrofuran, reacting for 0.5h at 50 ℃, concentrating and drying again, adding the same volume of 2-methyltetrahydrofuran for 1 time to obtain a concentrate (an intermediate with three acetyl protection removed), adding the concentrate into 550mL of 2-methyltetrahydrofuran for heating and dissolving, transferring into the reaction bottle, adding 62g of sodium hydroxide and 9.6g of tetrabutylammonium iodide, heating to reflux, reacting for 0.5h, removing a stock solution in a water separator, diluting 126.6g of benzyl bromide with 300mL of 2-methyltetrahydrofuran, slowly adding into the reaction bottle, dropwise adding for 3h, reacting for 8h under constant temperature, and detecting the concentrate by thin layer chromatography (developing solvent is DCM/MEOH 10/1; 2 mL; and adding 1 drop of acetic acid) to obtain pretreated product;
2) and (3) post-treatment: cooling the pretreated product obtained in the step S3 to 30 ℃, adding 200mL of ethyl acetate and 300mL of water with the temperature of 15 ℃, separating liquid, extracting the water phase for 1 time by using 100mL of ethyl acetate, combining organic phases, washing for 1 time by using 150mL of 1mol/L hydrochloric acid, washing for 1 time by using saturated saline, concentrating and drying, adding 50mL of 1, 4-dioxane into the obtained concentrate, concentrating and drying again, and obtaining a light yellow oily substance, namely the compound D139 g;
s4: and (3) heating and hydrolyzing the compound D by a sulfuric acid solution, an acetic acid solution and 1, 4-dioxane, and carrying out aftertreatment to obtain a compound E:
1) pretreatment: adding 139g of the compound D prepared in the step S3 and a sulfuric acid solution (102g of concentrated sulfuric acid is diluted into 350mL by water), an acetic acid solution (279g of acetic acid is diluted into 350mL of an 80% acetic acid aqueous solution by water) and 460mL of 1, 4-dioxane into a reaction bottle, heating to 100 ℃, carrying out reflux reaction for 12 hours, and detecting that the compound D basically disappears by thin layer chromatography (a developing agent is EA/PE (ether)/5/1; 2mL) to obtain a pretreated product;
2) and (3) post-treatment: cooling the pretreated product obtained in the step S4 to 25 ℃, adding 1L of water and 200mL of ethyl acetate, separating liquid, extracting the water phase with 200mL of ethyl acetate for 2 times, combining the ethyl acetate phases, washing with 100mL of water for 1 time in sequence, washing with 300mL of saturated sodium bicarbonate for 1 time, washing with 200mL of saturated saline for 1 time, concentrating and drying, adding an ethanol solution into the obtained concentrate, concentrating and drying to obtain a white-like solid, namely a compound E76.2 g;
s5: and (3) carrying out a swern oxidation reaction on the compound E to obtain a crude product of the compound F:
adding 400mL of DMSO into a reaction bottle, dropwise adding 200mL of anhydride at 25 ℃, dissolving 76.2g of the compound E obtained in the step S4 into 160mL of DMSO, dropwise adding into the reaction bottle, reacting at 25 ℃, detecting the substantial disappearance of the compound E by thin-layer chromatography (the developing agent is EA/PE (equal to 5/1; 2 mL)), pouring the reaction liquid into 2L of ice water for quenching reaction, stirring for 0.5h, extracting for 3 times by 200mL of ethyl acetate, washing the ethyl acetate phase for 2 times by using 100mL of sodium chloride aqueous solution with the mass fraction of 10%, washing for 1 time by 300mL of saturated sodium bicarbonate aqueous solution, washing for 1 time by 200mL of saturated saline, concentrating and drying to obtain a crude product of the compound F;
s6: and (4) adding the crude product of the compound F obtained in the step S5 into 200mL of ethanol, heating until the mixture is refluxed and dissolved, cooling for crystallization, and performing suction filtration to obtain 58.3g of a purified compound F.
Example 3 Synthesis method of a Ticagrelnet intermediate
A method of synthesizing a tylosin intermediate, the method comprising:
s1: taking a compound A as a raw material, performing primary hydroxyl iodination, performing acetylation reaction on acetic anhydride/triethylamine to obtain a pretreated product, and performing aftertreatment to obtain a compound B:
1) pretreatment: adding a compound A60g, 89g of triphenylphosphine, 29.4g of imidazole and 300mL of tetrahydrofuran into a reaction bottle, heating to reflux, adding 86.3g of iodine into 150mL of tetrahydrofuran for dissolving, slowly dropping into the reaction bottle for 3h, keeping the temperature for reaction for 0.8h after dropping is finished, cooling to 20 ℃ after the reaction is finished, adding 146g of pyridine, quickly dropping 189g of anhydride, controlling the temperature in a 35 ℃ water bath, reacting for 13h, sampling, detecting by thin-layer chromatography (a developing agent is DCM/MEOH 10/1; 2 mL; and then adding 1 drop of acetic acid), and detecting that the compound A basically disappears to obtain a pretreated product;
2) and (3) post-treatment: cooling the pretreated product obtained in the step S1 to 28 ℃, adding 720mL of ethyl acetate and 480mL of 10% sodium chloride aqueous solution by mass fraction, stirring for 10min, separating, washing the obtained organic phase for 1 time by using 360mL of 10% sodium chloride aqueous solution by mass fraction, wherein the sodium chloride aqueous solution contains 150mL of concentrated hydrochloric acid, washing the organic phase for 1 time by using 480mL of 10% sodium chloride aqueous solution by mass fraction (containing 24g of sodium thiosulfate pentahydrate), concentrating to remove the organic solvent, adding 400mL of isopropanol, performing suction filtration, washing the filter cake by using isopropanol, and drying to obtain a white solid, namely a compound B106 g;
s2: and (3) carrying out reduction reaction on the compound B to obtain a compound C:
106g of the compound B obtained in the step S1, 5g of palladium-on-carbon catalyst, 38.2g of diisopropylethylamine and 1L of methanol were put in a reaction flask, and H was introduced thereinto2Performing displacement reaction for 3 times, reacting at room temperature until compound B basically disappears by thin layer chromatography (developer EA/PE is 1/5; 2mL), filtering with diatomite, washing filter cake with methanol, concentrating and drying filtrate, pulping with 100mL methanol, filtering, drying filter cake to obtain white solid, and making compound C79 g;
s3: removing acetyl protection from the compound C through catalytic amount of sodium methoxide, then performing benzyl protection on a NaOH/BnBr system to obtain a pre-treated product, and performing post-treatment to obtain a compound D:
1) pretreatment: adding 79g of the compound C obtained in the step S2, 1.3g of sodium methoxide and 400mL of anhydrous methanol into a reaction bottle, stirring for 0.5h at 28 ℃, detecting that the compound C basically disappears by thin-layer chromatography (a developing agent is DCM/MEOH 10/1; 2 mL; 1 drop of acetic acid is added), adding 0.48g of water for quenching reaction, concentrating and drying, adding 100mL of 2-methyltetrahydrofuran, reacting for 0.5h at 40 ℃, concentrating and drying again, adding the same volume of 2-methyltetrahydrofuran for 1 time to obtain a concentrate (an intermediate with three acetyl protection removed), adding the concentrate into 550mL of 2-methyltetrahydrofuran for heating and dissolving, transferring into the reaction bottle, adding 62g of sodium hydroxide and 9.6g of tetrabutylammonium iodide, heating to reflux, reacting for 0.5h, removing a stock solution in a water separator, diluting 126.6g of benzyl bromide with 300mL of 2-methyltetrahydrofuran, slowly dropping into the reaction bottle, dropwise adding for 3h, reacting for 8h under constant temperature, and detecting the concentrate by thin layer chromatography (developing solvent is DCM/MEOH 10/1; 2 mL; and adding 1 drop of acetic acid) to obtain pretreated product;
2) and (3) post-treatment: cooling the pretreated product obtained in the step S3 to 25 ℃, adding 200mL of ethyl acetate and 300mL of water with the temperature of 12 ℃, separating liquid, extracting the water phase for 1 time by using 100mL of ethyl acetate, combining organic phases, washing for 1 time by using 150mL of 1mol/L hydrochloric acid, washing for 1 time by using saturated saline, concentrating and drying, adding 50mL of 1, 4-dioxane into the obtained concentrate, concentrating and drying again, and obtaining a light yellow oily substance which is the compound D140 g;
s4: and (3) heating and hydrolyzing the compound D by a sulfuric acid solution, an acetic acid solution and 1, 4-dioxane, and carrying out aftertreatment to obtain a compound E:
1) pretreatment: adding 140g of the compound D prepared in the step S3 and a sulfuric acid solution (102g of concentrated sulfuric acid is diluted into 350mL by water), an acetic acid solution (279g of acetic acid is diluted into an 80% acetic acid aqueous solution by water and 350mL is 460mL of 1, 4-dioxane into a reaction bottle, heating to 100 ℃, carrying out reflux reaction for 12h, and detecting that the compound D basically disappears by thin layer chromatography (a developing agent is EA/PE (5/1); 2mL) to obtain a pretreated product;
2) and (3) post-treatment: cooling the pretreated product obtained in the step S4 to 22 ℃, adding 1L of water and 200mL of ethyl acetate, separating liquid, extracting the water phase with 200mL of ethyl acetate for 2 times, combining the ethyl acetate phases, washing with 100mL of water for 1 time in sequence, washing with 300mL of saturated sodium bicarbonate for 1 time, washing with 200mL of saturated saline for 1 time, concentrating and drying, adding an ethanol solution into the obtained concentrate, concentrating and drying to obtain a white-like solid, namely a compound E79 g;
s5: and (3) carrying out a swern oxidation reaction on the compound E to obtain a crude product of the compound F:
adding 400mL of DMSO into a reaction bottle, dropwise adding 200mL of anhydride at 23 ℃, dissolving 79g of the compound E obtained in the step S4 into 160mL of DMSO, dropwise adding into the reaction bottle, reacting at 25 ℃, detecting the substantial disappearance of the compound E by thin-layer chromatography (the developing agent is EA/PE (equal to 5/1; 2 mL)), pouring the reaction solution into 2L of ice water for quenching reaction, stirring for 0.5h, extracting for 3 times by 200mL of ethyl acetate, washing the ethyl acetate phase for 2 times by using 100mL of sodium chloride aqueous solution with the mass fraction of 10%, washing for 1 time by using 300mL of saturated sodium bicarbonate solution, washing for 1 time by using 200mL of saturated saline, concentrating and drying to obtain a crude product of the compound F;
s6: and (4) adding the crude product of the compound F obtained in the step S5 into 200mL of ethanol, heating until the mixture is refluxed and dissolved, cooling for crystallization, and performing suction filtration to obtain 62g of a purified compound F.
Experimental example 1 yield of synthetic method of Tagliflozin intermediate
The yields of each reaction step and the total reaction yields of examples 1 to 3 are shown in Table 1.
Table 1: summary of yield and Total reaction yield for each step
As can be seen from table 1, the embodiment 3 is the best technical scheme provided by the present invention, and the total yield can reach 56%, and the present invention has significant progress.
Experimental example 2 purity and impurities of the intermediate of tylosin obtained by the synthesis
The purity and impurity content of the tagagliflozin intermediate obtained using the synthesis method of example 3 are shown in table 2. The chromatogram of the purity of the tagagliflozin intermediate obtained by the synthetic method of example 3 is shown in fig. 1, and the nuclear magnetic resonance spectrum is shown in fig. 2.
Table 2: example 3 purity and impurity content of the final dapagliflozin intermediate
| Detecting items | Example 3 |
| Purity of | 99.7％ |
| Content of impurities | Simple impurity<0.22％ |
As can be seen from table 2 and fig. 1, the purity of the tylosin intermediate synthesized in example 3 can reach 99.7%, and the purity of the monohetero (mainly dibenzyl ether) < 0.22%, which fully confirms that the synthetic route provided by the present invention can obtain a high-purity tylosin intermediate, and as can be seen from fig. 2, the tylosin intermediate synthesized in example 3 of the present invention is confirmed to be compound F, which has a wide application prospect.
Claims (8)
1. A synthetic method of a tylosin intermediate, which is characterized by comprising the following steps:
s1: taking a compound A as a raw material, performing iodination on primary hydroxyl, performing acetylation reaction on acetic anhydride/triethylamine to obtain a pretreated product, and performing aftertreatment to obtain a compound B;
s2: carrying out reduction reaction on the compound B to obtain a compound C;
s3: removing acetyl protection from the compound C through catalytic amount of sodium methoxide, performing benzyl protection on a NaOH/BnBr system to obtain a pre-treated product, and performing post-treatment to obtain a compound D;
s4: heating and hydrolyzing the compound D through a sulfuric acid solution, an acetic acid solution and 1, 4-dioxane to obtain a pretreated product, and performing aftertreatment to obtain a compound E;
s5: performing swern oxidation reaction on the compound E to obtain a crude product of a compound F;
s6: and (4) adding the crude product of the compound F obtained in the step S5 into ethanol, heating until the mixture is refluxed and dissolved, cooling for crystallization, and performing suction filtration to obtain a purified compound F, wherein the reaction formula is shown as follows:
in the step S3, the mass ratio of sodium methoxide used for deacetylation protection of the compound C by catalytic amount of sodium methoxide to the compound C is 1: 50-55.
2. The method for synthesizing the intermediate of tylosin according to claim 1, wherein the starting materials for preparing the compound B from the compound a in the step S1 include the compound a, triphenylphosphine, imidazole, tetrahydrofuran and iodine, the mass ratio of the compound a, triphenylphosphine and imidazole is 1.8-2.3:3:1, and the mass of iodine is 1.2-1.6 times that of the compound a.
3. The method for synthesizing a tylosin intermediate according to claim 1, wherein the post-treatment in step S1 is: cooling a product obtained after primary hydroxyl iodo and acetic anhydride/triethylamine acetylation reaction to 25-30 ℃, adding ethyl acetate and 10% by mass of sodium chloride aqueous solution, stirring for 10min, separating liquid, washing an organic phase for 1 time by using the 10% by mass of sodium chloride aqueous solution, wherein the sodium chloride aqueous solution contains 30-50% by volume of concentrated hydrochloric acid, washing the organic phase for 1 time by using the aqueous solution containing sodium thiosulfate pentahydrate and sodium chloride, concentrating to remove an organic solvent, adding isopropanol, performing suction filtration, washing a filter cake by using the isopropanol, and drying to obtain a compound B.
4. The method for synthesizing the intermediate of tylosin according to claim 1, wherein the step of reducing compound B to obtain compound C in step S2 comprises the steps of adding compound B obtained in step S1, palladium on carbon catalyst, diisopropylethylamine and methanol into a reaction flask, and introducing H2The displacement reaction is carried out for 3 times;
or adding the compound B prepared in the step S1, water and zinc powder into a reaction bottle, dropwise adding acetic acid to react completely, performing suction filtration, washing a filter cake with ethyl acetate, extracting a filtrate for 1 time with ethyl acetate, washing an ethyl acetate phase for 1 time with water, washing saturated sodium bicarbonate for 1 time, washing with saturated saline for 1 time, concentrating and drying, pulping a solid with methanol, performing suction filtration, and drying the filter cake to obtain a white solid C, thus preparing the compound C.
5. The method for synthesizing a tylosin intermediate according to claim 1, wherein the post-treatment in step S3 is: and (3) cooling the product pretreated in the step (S3) to 25-30 ℃, adding ethyl acetate and water with the temperature of 10-15 ℃, separating liquid, extracting the water phase for 1 time by using ethyl acetate, combining organic phases, washing for 1 time by using hydrochloric acid, washing for 1 time by using saturated saline solution, concentrating and drying, adding 1, 4-dioxane into the obtained concentrate, concentrating and drying again to obtain the compound D.
6. The method for synthesizing a tylosin intermediate according to claim 1, wherein the reaction of hydrolyzing the compound D by heating with sulfuric acid solution, acetic acid solution and 1, 4-dioxane in step S4 requires heating to 100 ℃ and refluxing for 10-12 h.
7. The method for synthesizing a tylosin intermediate according to claim 1, wherein the post-treatment in step S4 is: and (3) cooling the product pretreated in the step S4 to 20-25 ℃, adding water and ethyl acetate, separating liquid, extracting the water phase with ethyl acetate for 2 times, combining the ethyl acetate phases, washing with water for 1 time, washing with saturated sodium bicarbonate for 1 time, washing with saturated salt solution for 1 time, concentrating and drying, adding ethanol into the obtained concentrate, concentrating and drying to obtain the compound E.
8. The method for synthesizing the tylosin intermediate according to claim 1, wherein the step of swern oxidation reaction in the step S5 comprises: and (3) adding DMSO (dimethyl sulfoxide) into a reaction bottle, controlling the temperature to be 20-25 ℃, dropwise adding anhydride, dissolving the compound E obtained in the step S4 into the DMSO, and then dropwise adding the compound E into the reaction bottle to react at 20-25 ℃.
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