CN115974953A - Recovery method of fulvestrant - Google Patents
Recovery method of fulvestrant Download PDFInfo
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- CN115974953A CN115974953A CN202211738233.2A CN202211738233A CN115974953A CN 115974953 A CN115974953 A CN 115974953A CN 202211738233 A CN202211738233 A CN 202211738233A CN 115974953 A CN115974953 A CN 115974953A
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Abstract
The invention discloses a method for recovering fulvestrant, which aims at recovering fulvestrant with unqualified isomers. The method adopts fulvestrant with unqualified sulfoxide configuration proportion as raw material, and carries out reaction of reducing sulfoxide group into thioether, and then oxidizes the thioether into sulfoxide through oxidation reaction. By adopting the method, the recovery rate of fulvestrant with unqualified isomer ratio reaches about 77.3 percent, so that the utilization rate of raw materials is greatly improved, the industrial production cost is greatly reduced, the serious three-waste discharge is well solved, and the method is favorable for industrial popularization.
Description
Technical Field
The invention relates to a preparation method of fulvestrant with unqualified recovered isomer ratio, belonging to the technical field of pharmaceutical chemistry.
Background
Fulvestrant, a novel class of selective estrogen receptor down-regulator, received FDA approval in the united states for marketing in 2002, 4 months, and has received increasing attention from the industry. The market of fulvestrant opens up the field of small molecule drug therapy for inducing protein degradation, the fulvestrant acts like an enzyme or a catalyst, and the protein degradation is caused after the fulvestrant is combined with a target protein, and the fulvestrant is not consumed. The action mechanism of the polypeptide completely inhibits an Estrogen Receptor (ER) signaling pathway, can combine, block and down-regulate the ER with high affinity, inactivates a transcription Activation Function (AF) 1 and an AF2 on the hormone receptor, accelerates the degradation and loss of the ER, and becomes a new choice for the internal division therapy of the breast cancer. With the confirmation of various clinical studies, the curative effect of fulvestrant single-drug or combined targeted drug treatment is confirmed in clinic. Fulvestrant has the structural formula:
the two isomeric structural formulae of fulvestrant are:
fulvestrant currently in clinical use is a mixture of two diastereomers and the isomers a: B =42:58 to 48:52.
because the yield of the existing fulvestrant synthesis process is not high at present, and more isomers exist in the mother liquor with unqualified proportion, fulvestrant can not be used as a raw material, if the mother liquor is not recycled, the utilization rate of the raw material is low, the industrial cost is greatly improved, and the three wastes are seriously discharged.
Disclosure of Invention
The invention aims to solve the defects of the prior art, reduce the waste of raw materials, improve the utilization rate of the raw materials, reduce the production cost and reduce the discharge amount of three wastes, and provides a method for recovering fulvestrant unqualified due to isomers.
Aiming at the problems, the adopted specific scheme is as follows:
a fulvestrant recovery method comprises the following steps:
(1) Reduction reaction
a) Adding fulvestrant mother liquor into a reaction bottle to recover a crude product and a polar solvent, and stirring for dissolving;
b) Cooling the solution to-10-0 ℃; under the protection of nitrogen, dropwise adding a BH3/THF solution into a reaction bottle while stirring, and controlling the temperature to be-10-0 ℃; heating the obtained mixed solution to reflux; feeding equivalent ratio fulvestrant: BH3/THF =1:1 to 1:4;
c) Cooling the reaction liquid to V, dropwise adding methanol into the reaction liquid for quenching, and controlling the temperature to be-10-0 ℃; after the dripping is finished, stirring for 10-20 min; heating to room temperature and stirring for 10-20 min;
d) Concentrating the reaction solution under reduced pressure; adding ethyl acetate into the concentrated solution for dissolving;
e) Adding a sodium hydroxide aqueous solution into the solution to adjust the pH to be between 9 and 12, and stirring for 10 to 20min; standing for layering; adding 0.5-1.5 volume times of saturated sodium chloride aqueous solution into the organic phase after liquid separation, and stirring for 10-20 min; stirring for 10-20 min; standing and layering; after liquid separation, carrying out organic phase vacuum concentration to obtain a concentrated solution for next oxidation;
the reaction route is as follows:
(2) Oxidation reaction
Oxidizing thioether generated by the reduction reaction by using hydrogen peroxide in a polar solvent to obtain fulvestrant with qualified isomer ratio; the oxidant is hydrogen peroxide; the concentration of the hydrogen peroxide is 17-22 percent; the polar solvent is at least one selected from ethyl acetate, tetrahydrofuran, methanol and ethanol; the reaction temperature is 10-20 ℃.
The reaction route is as follows:
the above-mentioned fulvestrant recovery method further preferably comprises the following steps: in the step (1) b), the mixed solution is heated and refluxed, and the reaction time is 1-2 h.
The above-mentioned fulvestrant recovery method further preferably comprises the following steps: in the step (1) a), the polar solvent is selected from one of methanol, ethanol and tetrahydrofuran; the mass-volume ratio of fulvestrant to polar solvent is 1:6g/ml.
The above-mentioned fulvestrant recovery method further preferably adopts the following technical scheme: in step (1) e), an aqueous sodium hydroxide solution is added to the solution to adjust the pH =10 to 11.
The above-mentioned fulvestrant recovery method further preferably comprises the following steps: in the step (1) b), the feeding equivalent ratio fulvestrant: BH3/THF =1:2.
the above-mentioned fulvestrant recovery method further preferably comprises the following steps: in the step (1) e), after liquid separation, 0.8-1.2 volume times of saturated sodium chloride aqueous solution is added into the organic phase and stirred for 10-20 min.
The invention also discloses another fulvestrant recovery method, which comprises the following steps:
(1) Reduction reaction
a) Adding fulvestrant mother liquor into a reaction bottle to recover a crude product, zinc powder and an acetic acid solution, and heating to reflux; the mass ratio of fulvestrant to zinc powder is 1: 0.75-1, wherein the mass-volume ratio of fulvestrant to glacial acetic acid is 1: 6-8 g/ml; the purity of the zinc powder is more than 99.999 percent;
b) After the reaction is finished, carrying out suction filtration, adding toluene into the reaction solution, controlling the reaction temperature to be below 10 ℃, dropwise adding water for liquid separation and extraction, washing the obtained organic phase with water, and concentrating under reduced pressure;
the reaction route is as follows:
(2) Oxidation reaction
Oxidizing thioether generated by the reduction reaction by using hydrogen peroxide in a polar solvent to obtain fulvestrant with qualified isomer ratio; the oxidant is hydrogen peroxide; the concentration of the hydrogen peroxide is 17% -22%; the polar solvent is at least one selected from ethyl acetate, tetrahydrofuran, methanol and ethanol; the reaction temperature is 10-20 ℃.
The oxidation reaction route is as follows:
in the invention, a further preferable technical scheme is that in the step (1) a), the mass ratio of fulvestrant to zinc powder is 1:1, the mass-to-volume ratio of fulvestrant to glacial acetic acid is 1:8g/ml.
Compared with the prior art, the invention has the following beneficial effects:
by adopting the method, the recovery rate of fulvestrant with unqualified isomer ratio reaches about 77.3 percent, so that the utilization rate of raw materials is greatly improved, the industrial production cost is greatly reduced, the serious three-waste discharge is well solved, and the method is favorable for industrial popularization.
Drawings
FIG. 1 is a high performance liquid chromatogram of fulvestrant isomer ratio of specific example 1;
wherein label a is fulvestrant isomer a; notation B is fulvestrant isomer B isomer a isomer B =44.8/55.2.
Figure 2 is a high performance liquid chromatogram of fulvestrant-related substance of specific example 1, wherein the fulvestrant purity is 99.96%.
FIG. 3 is a high performance liquid chromatogram of fulvestrant isomer ratio of specific example 2;
wherein label a is fulvestrant isomer a; notation B is fulvestrant isomer B isomer a isomer B =47.0/53.0.
FIG. 4 is a high performance liquid chromatogram of fulvestrant-related substance of example 2; wherein the fulvestrant purity is 99.83%.
FIG. 5 is a high performance liquid chromatogram of fulvestrant isomer ratio of specific example 3;
wherein label a is fulvestrant isomer a; notation B is fulvestrant isomer B isomer a isomer B =45.4/54.6.
FIG. 6 is a high performance liquid chromatogram of fulvestrant-related substance of example 3; wherein the fulvestrant purity is 99.91%.
Detailed Description
The present invention is further illustrated by the following examples, but various substitutions and alterations and changes in proportion, which are made by ordinary technical knowledge and ordinary skill in the art, are included in the scope of the present invention.
Example 1:
(1) Reduction reaction
Weighing 10g of fulvestrant mother liquor recovered crude product and 70ml of tetrahydrofuran, adding into a 250ml three-necked bottle, and stirring for dissolving; cooling the reaction solution to 0 ℃; under the protection of nitrogen, measuring 32ml of BH3/THF solution, dropwise adding into a reaction bottle while stirring, controlling the temperature to be 0 ℃, heating and refluxing the obtained mixed solution, and reacting for 1h; cooling the reaction solution to 0 ℃; 20ml of methanol is dripped into the reaction solution for quenching, and the temperature is lower than 0 ℃; after the dropwise addition is finished, stirring for 15min; heating to room temperature and stirring for 15min; concentrating the reaction solution under reduced pressure; adding 50ml of ethyl acetate into the concentrated solution for dissolving; adding a 15% sodium hydroxide aqueous solution into the solution to adjust the pH to be =9, and stirring for 15min; standing and layering; adding saturated sodium chloride aqueous solution into the organic phase after liquid separation, and stirring for 15min; standing and layering; and (4) after liquid separation, carrying out pressure concentration on the organic phase to obtain a concentrated solution for next oxidation.
(2) Oxidation reaction
Adding 60ml of ethyl acetate into the concentrated solution obtained in the last step, stirring and dissolving the solution to be clear, adding 6.1g of acetic acid and 6.8g21% of hydrogen peroxide, controlling the reaction temperature to be 10-20 ℃ for reaction for 9 hours, controlling the temperature to be not more than 30 ℃, dropwise adding a sodium sulfite solution until the potassium iodide starch test paper is not bluish, dropwise adding a 28.3g15% sodium hydroxide aqueous solution, and controlling the temperature to be not more than 30 ℃; preserving the heat for 30 minutes; separating, washing the organic phase with 20ml water twice, concentrating under reduced pressure with 55 deg.C water bath, refining with ethyl acetate to obtain white solid 7.73g, detecting by high performance liquid chromatography, isomer A, isomer B =44.8/55.2, purity is 99.96%, and the total yield of the two-step reaction is 77.3% as shown in figure 1 and figure 2.
Example 2:
(1) Reduction reaction
Weighing 10g of fulvestrant mother liquor recovered crude product and 65ml of tetrahydrofuran, adding into a 250ml three-necked bottle, and stirring for dissolving; cooling the reaction liquid to-5 ℃; under the protection of nitrogen, measuring 35ml of BH3/THF solution, dropwise adding into a reaction bottle while stirring, controlling the temperature to be lower than-5 ℃, heating and refluxing the obtained mixed solution, and reacting for 1h; cooling the reaction solution to-5 ℃; 20ml of methanol is dripped into the reaction solution for quenching at the temperature of minus 5 ℃; after the dropwise addition is finished, stirring for 20min; heating to room temperature and stirring for 20min; concentrating the reaction solution under reduced pressure; adding 50ml of ethyl acetate into the concentrated solution for dissolving; adding a 15% sodium hydroxide aqueous solution into the solution to adjust the pH to be =10, and stirring for 20min; standing for layering; adding saturated sodium chloride aqueous solution into the organic phase after liquid separation, and stirring for 10-20 min; standing for layering; and (4) after liquid separation, carrying out pressure concentration on the organic phase to obtain a concentrated solution for next oxidation.
(2) Oxidation reaction
Adding 60ml of ethyl acetate into the concentrated solution obtained in the last step, stirring and dissolving the mixture to be clear, adding 6.0g of acetic acid and 6.5g of 21% hydrogen peroxide, controlling the reaction temperature to be 10-20 ℃ for reaction for 9 hours, controlling the temperature to be not more than 30 ℃, dropwise adding a sodium sulfite solution until the starch potassium iodide test paper does not turn blue, dropwise adding a 25.0g of 15% sodium hydroxide aqueous solution, and controlling the temperature to be not more than 30 ℃; preserving the heat for 30 minutes; separating, washing the organic phase with 20ml water twice, concentrating under reduced pressure with 55 deg.C water bath, refining with ethyl acetate to obtain white solid 7.16g, detecting by high performance liquid chromatography, isomer A, isomer B =47.0/53.0, purity is 99.96%, and the total yield of the two-step reaction is 71.6% as shown in figure 3 and figure 4.
Example 3:
(1) Reduction reaction
Weighing 10g of fulvestrant mother liquor recovered crude product and 7.5g of zinc powder, adding 80ml of glacial acetic acid into a 250ml three-mouth bottle, and stirring for dissolving; heating to reflux and reacting for 10h; filtering; adding 50ml of toluene into the reaction solution, and reducing the temperature to below 10 ℃; dropwise adding 50ml of water, and separating liquid; washing the organic phase with 50ml water for three times, and concentrating the reaction solution under reduced pressure in a water bath at 60 ℃; the concentrated solution is used for the next oxidation. The step is characterized in that the purity of the zinc powder needs to reach 99.999 percent.
(2) Oxidation reaction
In the same manner as in example 1, 6.02g of a white solid having an acceptable isomer ratio (isomer a: isomer B = 45.4/54.6) was obtained with a purity of 99.91%, as shown in fig. 5 and 6. The total yield of the two steps is 60.2%.
Claims (8)
1. A fulvestrant recovery method is characterized by comprising the following steps:
(1) Reduction reaction
a) Adding fulvestrant mother liquor into a reaction bottle to recover a crude product and a polar solvent, and stirring for dissolving;
b) Cooling the solution to-10-0 ℃; under the protection of nitrogen, dropwise adding the BH3/THF solution into a reaction bottle while stirring, and controlling the temperature to be-10-0 ℃; heating the obtained mixed solution to reflux; feeding equivalent ratio fulvestrant: BH3/THF =1:1 to 1:4;
c) Cooling the reaction liquid to V, dropwise adding methanol into the reaction liquid for quenching, and controlling the temperature to be-10-0 ℃; after the dropwise addition is finished, stirring for 10-20 min; heating to room temperature and stirring for 10-20 min;
d) Concentrating the reaction solution under reduced pressure; adding ethyl acetate into the concentrated solution for dissolving;
e) Adding sodium hydroxide aqueous solution into the solution to adjust the pH to be between 9 and 12, and stirring for 10 to 20min; standing for layering; adding 0.5-1.5 volume times of saturated sodium chloride aqueous solution into the organic phase after liquid separation, and stirring for 10-20 min; stirring for 10-20 min; standing and layering; after liquid separation, carrying out organic phase vacuum concentration to obtain a concentrated solution for next oxidation;
(2) Oxidation reaction
Oxidizing thioether generated by the reduction reaction by using hydrogen peroxide in a polar solvent to obtain fulvestrant with qualified isomer ratio; the oxidant is hydrogen peroxide; the concentration of the hydrogen peroxide is 17-22%; the polar solvent is at least one selected from ethyl acetate, tetrahydrofuran, methanol and ethanol; the reaction temperature is 10-20 ℃.
2. The method for recovering fulvestrant according to claim 1, wherein in step (1) b), the mixed solution is heated under reflux for 1-2 hours.
3. The method for recovering fulvestrant according to claim 1, wherein in step (1) a), the polar solvent is selected from one of methanol, ethanol and tetrahydrofuran; the mass volume ratio of fulvestrant to polar solvent is 1:6g/ml.
4. The method for recovering fulvestrant according to claim 1, wherein in step (1) e), an aqueous sodium hydroxide solution is added to the solution to adjust the pH =10 to 11.
5. A process for the recovery of fulvestrant according to claim 1 wherein in step (1) b) the feed equivalents are such that the ratio of fulvestrant: BH3/THF =1:2.
6. the method for recovering fulvestrant according to claim 1, wherein in step (1) e), after the liquid separation, 0.8 to 1.2 volume times of saturated aqueous sodium chloride solution is added to the organic phase and stirred for 10 to 20 minutes.
7. A fulvestrant recovery method is characterized by comprising the following steps:
(1) Reduction reaction
a) Adding fulvestrant mother liquor into a reaction bottle to recover a crude product, zinc powder and an acetic acid solution, and heating to reflux; the mass ratio of fulvestrant to zinc powder is 1: 0.75-1, wherein the mass-volume ratio of fulvestrant to glacial acetic acid is 1: 6-8 g/ml; the purity of the zinc powder is more than 99.999 percent;
b) After the reaction is finished, carrying out suction filtration, adding toluene into the reaction solution, controlling the reaction temperature to be below 10 ℃, dropwise adding water for liquid separation extraction, washing the obtained organic phase with water, and concentrating under reduced pressure;
(2) Oxidation reaction
Oxidizing thioether generated by the reduction reaction by using hydrogen peroxide in a polar solvent to obtain fulvestrant with qualified isomer ratio; the oxidant is hydrogen peroxide; the concentration of the hydrogen peroxide is 17% -22%; the polar solvent is at least one selected from ethyl acetate, tetrahydrofuran, methanol and ethanol; the reaction temperature is 10-20 ℃.
8. The method as claimed in claim 7, wherein in the step (1) a), the mass ratio of fulvestrant to zinc powder is 1:1, the mass-to-volume ratio of fulvestrant to glacial acetic acid is 1:8g/ml.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103788164A (en) * | 2012-10-31 | 2014-05-14 | 正大天晴药业集团股份有限公司 | Preparation method of fulvestrant |
| CN106146599A (en) * | 2015-04-07 | 2016-11-23 | 江苏希迪制药有限公司 | A kind of recovery is because of the method for sulfoxide configuration ratio underproof fulvestrant or derivatives thereof |
| CN107033210A (en) * | 2016-02-03 | 2017-08-11 | 正大天晴药业集团股份有限公司 | A kind of preparation method of fulvestrant and its intermediate |
| CN107698647A (en) * | 2017-09-21 | 2018-02-16 | 杭州新博思生物医药有限公司 | A kind of improved method for reclaiming the underproof fulvestrant of isomer proportion |
| CN114685593A (en) * | 2020-12-31 | 2022-07-01 | 鲁南制药集团股份有限公司 | Fulvestrant preparation method and intermediate thereof |
| US20220259257A1 (en) * | 2021-02-12 | 2022-08-18 | Farmabios S.P.A. | Process for the preparation of fulvestrant |
| CN115448971A (en) * | 2021-06-09 | 2022-12-09 | 上海弼领生物技术有限公司 | Intermediate for preparing fulvestrant and preparation method thereof |
-
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- 2022-12-30 CN CN202211738233.2A patent/CN115974953B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103788164A (en) * | 2012-10-31 | 2014-05-14 | 正大天晴药业集团股份有限公司 | Preparation method of fulvestrant |
| CN106146599A (en) * | 2015-04-07 | 2016-11-23 | 江苏希迪制药有限公司 | A kind of recovery is because of the method for sulfoxide configuration ratio underproof fulvestrant or derivatives thereof |
| CN107033210A (en) * | 2016-02-03 | 2017-08-11 | 正大天晴药业集团股份有限公司 | A kind of preparation method of fulvestrant and its intermediate |
| CN107698647A (en) * | 2017-09-21 | 2018-02-16 | 杭州新博思生物医药有限公司 | A kind of improved method for reclaiming the underproof fulvestrant of isomer proportion |
| CN114685593A (en) * | 2020-12-31 | 2022-07-01 | 鲁南制药集团股份有限公司 | Fulvestrant preparation method and intermediate thereof |
| US20220259257A1 (en) * | 2021-02-12 | 2022-08-18 | Farmabios S.P.A. | Process for the preparation of fulvestrant |
| CN115448971A (en) * | 2021-06-09 | 2022-12-09 | 上海弼领生物技术有限公司 | Intermediate for preparing fulvestrant and preparation method thereof |
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