阅读说明：本技术 一种合成他氟前列素的方法 (Method for synthesizing tafluprost ) 是由 杨君 于 2021-10-19 设计创作，主要内容包括：本发明提供一种合成他氟前列素的方法,涉及合成他氟前列素技术领域。该合成他氟前列素的方法,包括以下具体制备步骤：S1.初步反应,S2.二次反应,S3.三次反应,S4.四次反应,S5.五次反应,S6.最终反应。本发明提供一种合成他氟前列素的方法,该合成他氟前列素的方法以消旋的科立内酯二醇为原料,经氧化、缩合、氟化、还原、再缩合、酯化反应,得到他氟前列素,本发明的制备方法六步反应的总质量收率可达22％,工艺稳定,制备得到的他氟前列素产品为无色粘稠油状液体,纯度高达99％以上。(The invention provides a method for synthesizing tafluprost, and relates to the technical field of synthesis of tafluprost. The method for synthesizing tafluprost comprises the following specific preparation steps: s1, primary reaction, S2, secondary reaction, S3, tertiary reaction, S4, quaternary reaction, S5, quintic reaction and S6, final reaction. The invention provides a method for synthesizing tafluprost, which takes racemic Coryli lactone diol as a raw material and obtains the tafluprost through oxidation, condensation, fluorination, reduction, recondensation and esterification reaction.)

1. A method of synthesizing tafluprost, comprising: the method comprises the following specific preparation steps:

s1. preliminary reaction

Obtaining a primary medicament by oxidation reaction of an original compound;

s2. secondary reaction

Carrying out a horner-Watts-Eimers reaction on the primary medicament compound to obtain a secondary reaction compound;

s3, three reactions

Carrying out fluorination reaction on the secondary reaction compound under the action of a fluorination reagent to obtain a tertiary reaction compound;

s4, four reactions

Carrying out reduction reaction on the three reaction compounds to obtain four reaction compounds;

s5, five times of reaction

The fifth reaction compound is obtained by carrying out ylide reaction on the fourth reaction compound under the action of the compound;

s6, final reaction

And (3) carrying out esterification reaction on the compound and isopropyl iodide five times to obtain the tafluprost.

2. The method of claim 1, wherein the step of synthesizing tafluprost comprises: in the S2, a side chain is connected in a horner-Watts-Eimers reaction, and the used oxidant is selected from a dessimutan oxidant, a PCC oxidant, a PDC oxidant, a Swern oxidant, NaClO/TEMPO, manganese dioxide and other alcohol oxidants.

3. The method of claim 1, wherein the step of synthesizing tafluprost comprises: the reaction solvent used for linking the side chain in the horner-Watts-Emont reaction in S2 is selected from one or more of the following: tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1, 2-dichloroethane, acetonitrile, 1, 4-dioxane, dimethylformamide, dimethylacetamide or dimethylsulfoxide.

4. The method of claim 1, wherein the step of synthesizing tafluprost comprises: in the step S2, the horner-Watts-Eimers condensation reaction is carried out, and the used alkaline reagent is selected from sodium hydride, sodium tert-butoxide and potassium tert-butoxide.

5. The method of claim 1, wherein the step of synthesizing tafluprost comprises: the fluorinating reagent used in the fluorination reaction in S3 is selected from bis- (2-methoxyethyl) amino sulfur trifluoride, diethylamino sulfur trifluoride, sulfur trifluoride or sulfur trifluoride morpholine, and the solvent used is selected from dichloromethane, 1, 2-dichloroethane, chloroform or toluene.

6. The method of claim 1, wherein the step of synthesizing tafluprost comprises: in the reduction reaction in the step S4, the reducing agent is selected from diisobutylaluminum hydride, sodium borohydride or potassium borohydride; the reduction reaction is carried out in a dry aprotic solvent.

7. The method of claim 1, wherein the step of synthesizing tafluprost comprises: the base used in S5 is selected from potassium tert-butoxide, sodium hexamethyldisilazide or lithium hexamethyldisilazide, and the ylide reaction is carried out in an aprotic solvent.

8. The method of claim 1, wherein the step of synthesizing tafluprost comprises: in the esterification reaction in S6, the used base comprises an organic base and an inorganic base, the organic base comprises DBU, N-diisopropylethylamine or diisopropylamine, and the inorganic base comprises hydroxide and carbonate of alkali metal; the solvent used includes acetone, butanone, tetrahydrofuran, DMF, dichloromethane, ethanol, isopropanol or acetonitrile.

Technical Field

The invention relates to the technical field of synthesis of tafluprost, in particular to a method for synthesizing tafluprost.

Background

Tafluprost is a novel prostaglandin analogue mainly used for treating open-angle glaucoma or ocular hypertension of patients with elevated intraocular pressure, the main ocular hypotensive action mechanism is to promote the outflow of aqueous humor through uveoscleral to lower the intraocular pressure, the 15 th hydroxyl group in the structure of the traditional prostaglandin analogue is an essential functional group for exerting the physiological activity of a prostaglandin receptor agonist, the functional group is replaced by 2F atoms by the tafluprost, the tafluprost can be rapidly hydrolyzed into a free acid form by corneal esterase, namely an active form of the compound, and the affinity of the tafluprost to FP receptors of iris ciliary bodies is about 12 times stronger than that of a carboxylic acid product of the latprost.

In the prior patent (CN103804195B), CoreyLactone is properly protected and then subjected to DIBAL reduction, Wittig reaction, carboxyl protection and Swern oxidation to obtain a general intermediate compound 1, the intermediate 1 is used as a raw material, tafluprost and a plurality of intermediate products are obtained through several steps of reactions, the intermediate 1 can be connected with different omega chains to synthesize other various prost analogs, such as misoprost, travoprost, latanoprost and the like, and 2-4 can also be used for synthesizing other 16-phenoxyprost. However, although the method can be used for manufacturing, the preparation method has the advantages of long route, low atom utilization rate, expensive raw materials and large solvent dosage due to protection and deprotection, so that the production period of the tafluprost is long and the cost is high.

Disclosure of Invention

Technical problem to be solved

Aiming at the defects of the prior art, the invention provides a method for synthesizing tafluprost, which solves the problems of high cost, low purity and low production efficiency.

(II) technical scheme

In order to achieve the purpose, the invention is realized by the following technical scheme: a method for synthesizing tafluprost comprises the following specific preparation steps:

s1. preliminary reaction

Obtaining a primary medicament by oxidation reaction of an original compound;

s2. secondary reaction

Carrying out a horner-Watts-Eimers reaction on the primary medicament compound to obtain a secondary reaction compound;

s3, three reactions

Carrying out fluorination reaction on the secondary reaction compound under the action of a fluorination reagent to obtain a tertiary reaction compound;

s4, four reactions

Carrying out reduction reaction on the three reaction compounds to obtain four reaction compounds;

s5, five times of reaction

The fifth reaction compound is obtained by carrying out ylide reaction on the fourth reaction compound under the action of the compound;

s6, final reaction

And (3) carrying out esterification reaction on the compound and isopropyl iodide five times to obtain the tafluprost.

Preferably, in the step S2, the side chain is linked by a horner-Watts-Emmons reaction, and the oxidant used is selected from a desmartin oxidant, a PCC oxidant, a PDC oxidant, a Swern oxidant, NaClO/TEMPO, manganese dioxide and other alcohol oxidants.

Preferably, the reaction solvent used for the side chain attachment in the horner-watsworth-emmons reaction in S2 is selected from one or more of the following: tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1, 2-dichloroethane, acetonitrile, 1, 4-dioxane, dimethylformamide, dimethylacetamide or dimethylsulfoxide.

Preferably, in the S2 Horner-Watts-Eimers condensation reaction, the alkaline reagent is selected from sodium hydride, sodium tert-butoxide and potassium tert-butoxide.

Preferably, the fluorinating reagent used in the fluorination reaction in S3 is selected from bis- (2-methoxyethyl) aminosulfur trifluoride, diethylaminosulfur trifluoride, sulfur trifluoride or sulfur trifluoride morpholine, and the solvent used is selected from dichloromethane, 1, 2-dichloroethane, chloroform or toluene.

Preferably, the reduction reaction in S4 is carried out by using a reducing agent selected from diisobutylaluminum hydride, sodium borohydride or potassium borohydride; the reduction reaction is carried out in a dry aprotic solvent.

Preferably, the base used in S5 is selected from potassium tert-butoxide, sodium hexamethyldisilazide or lithium hexamethyldisilazide, and the ylide reaction is carried out in an aprotic solvent.

Preferably, in the esterification reaction in S6, the base used comprises organic base and inorganic base, the organic base comprises DBU, N-diisopropylethylamine or diisopropylamine, and the inorganic base comprises hydroxide and carbonate of alkali metal; the solvent used includes acetone, butanone, tetrahydrofuran, DMF, dichloromethane, ethanol, isopropanol or acetonitrile.

(III) advantageous effects

The invention provides a method for synthesizing tafluprost. The method has the following beneficial effects:

the invention provides a method for synthesizing tafluprost, which is a preparation method of a raw material drug of the tafluprost, the adopted raw material of a compound has controllable quality of starting materials, the subsequent reaction does not need the operation of protecting group application and protecting group removal, the atom economy is greatly improved, the reaction condition is accurately controlled, the yield of the compound in the formula 1 in the oxidation process is more than 95 percent, the content of trans-isomer impurities generated in the reduction reaction process of the compound in the formula 5 is less than 1 percent, the content of trans-isomer impurities generated in the wittig reaction process of the compound in the formula 6 is less than 1 percent, the mass yield of six steps of the whole process is 22 percent, and the purity of the obtained raw material drug is more than 99 percent.

Drawings

FIG. 1 is a chemical reaction scheme of S1 according to the present invention;

FIG. 2 is a chemical reaction formula of S2 according to the present invention;

FIG. 3 is a chemical reaction formula of S3 according to the present invention;

FIG. 4 is a chemical reaction formula of S4 according to the present invention;

FIG. 5 is a chemical reaction formula of S5 according to the present invention;

FIG. 6 shows the chemical reaction scheme of S6 according to the present invention.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

Example (b):

as shown in fig. 1 to 6, the embodiment of the present invention provides a method for synthesizing tafluprost, which comprises the following specific preparation steps:

s1, carrying out primary reaction, carrying out oxidation reaction on an original compound to obtain a primary medicament, specifically, adding 9.0g of NaOCl oxidant, 1.2eq of NaOCl oxidant, 1.5g of TEMPO catalyst, 0.1eq of the NaBr11.7g of NaBr11, 1.0eq of the NaOCl oxidant into DCM100mL, stirring for 15 minutes, cooling to-10-0 ℃, dropwise adding 17.2g of DCM100mL solution of the compound shown in the formula 1 into the reaction mixture, keeping the temperature at-10-0 ℃ for stirring for 3 hours, adding DCM300mL for dilution, adding 10% of sodium thiosulfate aqueous solution for quenching, keeping the temperature at 0-10 ℃ for continuous stirring for 1 hour, carrying out liquid separation, combining organic phases, and drying the organic phases through anhydrous sodium sulfate to obtain the primary medicament;

s2, performing secondary reaction, namely performing a horner-WobzWorts-Eimens reaction on a primary medicament compound to obtain a secondary reaction compound, namely adding 60% sodium hydride to 28.4g of the primary medicament compound and 1.1eq of DCM150mL solution in batches at-10-0 ℃, stirring for 1h, cooling to-30 ℃, dropwise adding the compound solution of the formula 2 prepared in example 1, stirring for 12h at-30 ℃, dropwise adding 20mL of 10% acetic acid aqueous solution, quenching, adjusting the pH of an aqueous phase to be 4, standing for layering, extracting the aqueous phase with DCM200mL, combining organic phases, drying with anhydrous sodium sulfate, concentrating the organic phase under reduced pressure to remove DCM, adding 40mL of ethanol into the residue, heating to reflux, stirring for 30min, cooling to-10-0 ℃, stirring for 12h, filtering, drying in vacuum to obtain 20.2g of a white solid, and obtaining a yield of 67.3%, is a secondary reaction compound;

s3, carrying out tertiary reaction, carrying out fluorination reaction on a secondary reaction compound under the action of a fluorination reagent to obtain a tertiary reaction compound, specifically, adding 30.0g of the secondary reaction compound into DCM300mL at-20-10 ℃, adding 1.6g of triethylamine trihydrofluoride salt, 0.1eq, dropwise adding DAST19.3g and 1.2eq, after dropwise adding is finished for about 12 hours, stirring and reacting for 3 days at-20-10 ℃, dropwise adding the reaction solution into 10% NaHCO3 for carrying out counter quenching, controlling the temperature to be 0-10 ℃, standing and layering, washing an organic phase with saturated NaCl50mL, drying anhydrous sodium sulfate, concentrating under reduced pressure to remove DCM to obtain a crude product, and directly obtaining the tertiary reaction compound without purification;

s4, carrying out four reactions, carrying out reduction reaction on a compound subjected to three reactions to obtain a compound subjected to four reactions, specifically, adding a crude product of the compound subjected to three reactions into 300mL of toluene, cooling to-40-30 ℃ under the protection of nitrogen, dropwise adding 80mL of a toluene solution of diisobutylaluminum hydride at 1.5mol/L, controlling the temperature in the dropwise adding process to-40-30 ℃, continuously stirring and reacting for 5 hours at the temperature after dropwise adding, adding 50mL of methanol for quenching reaction, filtering, washing a filter cake with 50mL of methanol, concentrating the filtrate under reduced pressure, adding 50mL of n-hexane into the residue, stirring and washing for 30 minutes, separating an n-hexane phase, dissolving the residue into DCM200mL, washing with 50mL of water, drying with anhydrous sodium sulfate, concentrating under reduced pressure to obtain a colorless oily substance, and directly obtaining the compound subjected to four reactions without purification;

s5, performing five-time reaction, namely performing ylide reaction on the four-time reaction compound under the action of the compound to obtain the five-time reaction compound, namely adding 50.0g of the four-time reaction compound 4-carboxybutyltriphenylphosphonium bromide and 2500mL of tetrahydrofuran into a reaction bottle, cooling to-30-20 ℃ under the protection of nitrogen, dropwise adding 150mL of a tetrahydrofuran solution of lithium bistrimethylsilyl amide into the reaction bottle at a concentration of 1mol/L, continuously stirring for 1 hour, dissolving a crude product of the compound 6 obtained in the example 4 by using 100mL of tetrahydrofuran, dropwise adding the dissolved product into the reaction solution, keeping the reaction temperature at-30-20 ℃ in the dropwise adding process, continuously stirring for 24 hours, pouring the reaction solution into 300mL of saturated ammonium chloride aqueous solution, adjusting the pH to 3-4 by using 2mol/L of citric acid, extracting by using 300mL of ethyl acetate, and extracting an organic phase by using water, Washed with saturated NaCl, dried over anhydrous sodium sulfate, concentrated under reduced pressure to give a yellow solid, which is purified by column chromatography, eluent ethyl acetate: n-hexane ═ 2:1 to 1: 2, obtaining 16.6g of a reaction compound for five times by volume, wherein the yield is 41.0%;

s6, carrying out final reaction, and carrying out esterification reaction on a fifth reaction compound and isopropyl iodide to obtain tafluprost, wherein specifically, 4.1g of the fifth reaction compound is dissolved in 50mL of DMF solution, the temperature is reduced to 0 ℃, 6.5g of cesium carbonate, 2.0eq and 3.4g of 2-iodopropane and 2.0eq are added, after reaction is carried out at 0 ℃ for 6 hours, 10% citric acid aqueous solution is added to adjust the pH to be 3-4, 100mL of ethyl acetate is added to extract, an organic phase is dried by anhydrous sodium sulfate, then is concentrated under reduced pressure and purified by column chromatography, and an eluent is ethyl acetate, namely n-hexane is 10: 1-3: 1, volume ratio, obtaining 2.9g of tafluprost with 80.2 percent of yield.

Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.