CN110818764A - Method for preparing fulvestrant intermediate by using charging monitoring system - Google Patents
Method for preparing fulvestrant intermediate by using charging monitoring system Download PDFInfo
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- CN110818764A CN110818764A CN201810889613.3A CN201810889613A CN110818764A CN 110818764 A CN110818764 A CN 110818764A CN 201810889613 A CN201810889613 A CN 201810889613A CN 110818764 A CN110818764 A CN 110818764A
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- VWUXBMIQPBEWFH-WCCTWKNTSA-N Fulvestrant Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=C1 VWUXBMIQPBEWFH-WCCTWKNTSA-N 0.000 title claims abstract description 34
- 229960002258 fulvestrant Drugs 0.000 title claims abstract description 33
- 238000012544 monitoring process Methods 0.000 title claims abstract description 26
- 238000000034 method Methods 0.000 title claims abstract description 21
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- 238000001514 detection method Methods 0.000 claims abstract description 35
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- 238000003756 stirring Methods 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- 239000000463 material Substances 0.000 claims description 9
- 239000011521 glass Substances 0.000 claims description 8
- 239000007818 Grignard reagent Substances 0.000 claims description 6
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 6
- 150000004795 grignard reagents Chemical class 0.000 claims description 6
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- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 5
- 229940045803 cuprous chloride Drugs 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
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- 241000227653 Lycopersicon Species 0.000 claims description 4
- 235000007688 Lycopersicon esculentum Nutrition 0.000 claims description 4
- 238000004821 distillation Methods 0.000 claims description 4
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 4
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- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 4
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
- C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
A charging monitoring system applied to real-time feedback of fulvestrant comprises a reaction device, a color detection module, a charging template and a main controller, wherein the reaction device is connected with the detection module and the charging module, the detection module and the charging module are connected with the main controller, and the main controller controls the operation of the detection module and the charging module through instructions; the main controller controls the feeding speed of the peristaltic pump through the received color digital information. The invention also provides a method for preparing the fulvestrant intermediate by using the charging monitoring system. The preparation method of the fulvestrant intermediate realizes online monitoring and comparison of the color of the reaction solution; compared with manual operation, the color of the reaction liquid can be more accurately identified, and the feeding speed of the feed liquid can be accurately controlled; the stability of the yield and purity of the fulvestrant intermediate preparation reaction is realized; the problems of large equipment operation error, long manual operation time and easy fatigue of operators in the prior art are solved, and the method has a wide application prospect.
Description
Technical Field
The invention relates to the field of medicines, in particular to a method for preparing a fulvestrant intermediate by using a charging monitoring system.
Background
Fulvestrant (Fulvestrant) is a steroid antiestrogen developed by Aslicon with the chemical name of 7 α - [9- (4,4,5,5, 5-pentafluoropentylsulfinyl) nonanyl ] estra-1,3, 5- (10) triene-3,17 β -diol with the chemical name of 7 α - [9- [ (4,4,5,5,5, -Pentafluoroxypentynyl) sulfenyl ] nonyl ] estra-1,3,5(10) -enetri-3, 17 β -diol with the chemical structure as follows:
fulvestrant is available in the form of an injection, approved by the FDA in the united states in 2002, under the trade name Faslodex, and is mainly used for the treatment of estrogen receptor positive metastatic breast cancer in postmenopausal women who are still worsening in disease due to anti-estrogen therapy, and currently has an average annual sales of $ 6.5 million. Experimental research shows that fulvestrant has no estrogen-like effect or anti-irritant effect of tamoxifen and partial agonistic activity on endometrium, so that adverse reaction is less than that of tamoxifen which is a similar medicine.
At present, the main synthetic route of fulvestrant is the one disclosed in patent CN01820270, the specific route is shown in fig. 1, in which the first step of the route is an addition reaction, which is a very critical step, which is a 1, 6-addition reaction catalyzed by cuprous chloride, addition of a grignard reagent and a dienone to form an adduct EAS, there is a cyclic process of oxidative addition-reductive elimination, the specific process is shown in fig. 2, in which the production of ketone adduct I is a reversible reaction, the reaction speed is fast, and the production of ketone adduct II is slow, which is a limiting step of the cyclic reaction. If the addition rate of the dienone is too high, the ketone addition product I is saturated in the solution, and the extra dienone outside the circulation can react with the Grignard reagent outside the circulation to generate 1, 2-addition byproducts, so that the purity of the intermediate EAS is low and the yield is low; if the addition of the dienone is too slow, a small amount of the adduct formed will decompose reversibly to the dienone, and the reaction will be terminated. Therefore, the feeding speed has an important influence on the yield and purity of the intermediate EAS under the premise of well controlling the feeding sequence and the reaction temperature.
At present, the general operation of the step in laboratories and industry is that Grignard reagent and cuprous chloride are stirred and cooled to about minus 30 ℃, a dienone solution is manually added, a ketone adduct I is an orange colored compound, the adding speed is judged and adjusted according to the color of reaction liquid, the adding time is long, operators are easy to tire, the color is judged by human eyes, so that large errors exist, and the repeating effect of different reaction batches is poor.
Based on the defects of the prior art, the technical personnel in the field are dedicated to developing an automatic feeding system capable of feeding back in real time, the use is convenient, and the reaction yield and the repeatability effect of the fulvestrant intermediate EAS are improved.
Disclosure of Invention
In view of the above-mentioned drawbacks of the prior art, the technical problems to be solved by the present invention are: 1. providing a charging system capable of objectively recognizing colors; 2. the color of the reaction solution can be monitored and compared on line; 3. controlling the feeding speed in real time through the comparison result; 4. the problem of among the prior art equipment operation error big, operating personnel is tired easily is improved.
In order to achieve the aim, the invention provides a charging monitoring system applied to real-time feedback of fulvestrant, which comprises a reaction device, a color detection module, a charging template and a main controller, wherein the reaction device is connected with the detection module and the charging module, the detection module and the charging module are connected with the main controller, and the main controller controls the operation of the detection module and the charging module through instructions;
the reaction device comprises a reactor, a stirrer, a temperature detector and inert gas inlet and outlet pipelines, and the reactor is a closed device except an inert gas flowing device;
the detection module comprises a color detection probe and a color identification converter electrically connected with the color detection probe; the color detection probe detects a color signal and sends the color signal to the color identification converter, and the color identification converter converts the color signal into digital information and sends the digital information to the main controller;
the feeding module comprises a speed-regulating peristaltic pump and a feeding device, the peristaltic pump and the feeding device are connected with the reactor through a feeding pipe, the peristaltic pump is connected with the main controller, and the main controller controls the feeding speed of the peristaltic pump through received color digital information.
Further, the main controller detects the color of the reaction liquid by using a color detection probe according to the set frequency.
Further, the reaction device comprises a glass reactor, a stainless steel reactor and an enamel reactor; the temperature detector is an alcohol thermometer, a probe type temperature detector or an infrared temperature detector. The stirrer comprises a magnetic stirrer and an electric mechanical stirrer. The inert gas is nitrogen or argon.
In a preferred embodiment of the invention, a glass reaction flask is used as a reactor, an alcohol low-temperature thermometer is used for controlling the temperature, an electric mechanical stirrer is used for stirring, and nitrogen is used as anhydrous oxygen-free protective gas.
Further, the connection mode of main control unit and colour discernment converter, main control unit and peristaltic pump is wired or wireless connection, and wireless connection can adopt bluetooth or wifi to connect.
Further, the main controller is a computer provided with a color comparison program or a mobile phone provided with a color comparison app. The main controller controls the speed of the peristaltic pump through color information, and the color information is mainly compared with the shades of orange-red series colors, and the method specifically comprises the following steps:
when the color of the reaction liquid is detected to be between light rose color and dark fresh meat color, the peristaltic pump feeds the materials at 100% of the set speed;
when the color of the reaction liquid is detected to be between the color of the dark fresh meat and the color of the tomato, the peristaltic pump feeds materials at 75% of the set speed;
when the color of the reaction liquid is detected to be between tomato red and orange red, a peristaltic pump feeds materials at 25% of a set speed;
when the color of the reaction liquid is detected to be between orange and red, the peristaltic pump stops feeding.
The main controller can also control the speed of the peristaltic pump in another mode, specifically:
the main controller records the bandwidth of the color change of the reaction liquid through manual operation reaction, records the lightest color point and the darkest color point, and linearly and uniformly adjusts the reaction speed according to the color of the reaction liquid in the subsequent reaction liquid feeding process;
when the detected reaction liquid is the lightest color point, the peristaltic pump feeds materials at 100% of the set speed;
when the color point of the reaction solution is the darkest, the peristaltic pump stops feeding.
The application further provides a method for preparing a fulvestrant intermediate by using the charging monitoring system, which comprises the following steps:
step 1, filling inert gas into a reactor with a temperature detector, a color detector and a stirrer, adding a Grignard reagent, putting the mixture into a refrigerator with a cold bath at-40 ℃, stirring the solution, cooling the solution to-35 ℃, adding cuprous chloride, and stirring.
And 2, starting a feeding monitoring system, setting detection frequency, starting a peristaltic pump, controlling the peristaltic pump to automatically add the dienone solution by the main controller through a program instruction, detecting the reaction by using HPLC after dripping, adding the acetic acid solution when the dienone proportion is less than 1%, and then returning to the room temperature for stirring after adding.
And 3, adding water into the reaction liquid at 0 ℃, adding an antioxidant, uniformly stirring, performing reduced pressure distillation to remove the reaction solvent, adding water and n-hexane, performing suction filtration, layering the filtrate, extracting the water layer once with n-hexane, combining the organic layers, washing once with a potassium chloride solution, drying, and performing reduced pressure distillation to obtain the fulvestrant EAS intermediate oily substance.
The invention provides a real-time feedback charging monitoring system, which is particularly used for preparing a medicinal intermediate with color change in the reaction process, in particular to the preparation of an antitumor medicament fulvestrant intermediate EAS. The invention can be used for laboratory pilot scale reaction, and can also be provided with a pilot scale reaction kettle and an amplification reaction kettle, and is applied to pilot scale and industrial production. Compared with the prior art, the preparation method and the feeding system of the fulvestrant EAS intermediate have the following effects:
1) the online monitoring comparison of the colors of the reaction solution is realized;
2) compared with manual operation, the color of the reaction liquid can be more accurately identified, and the feeding speed of the feed liquid can be accurately controlled;
3) the stability and the repeatability of the reaction yield and the purity of the step are realized;
4) the problems of large equipment operation error, long manual operation time and easy fatigue of operators in the prior art are solved, and the method has a wide application prospect.
The conception, the specific structure and the technical effects of the present invention will be further described with reference to the accompanying drawings to fully understand the objects, the features and the effects of the present invention.
Drawings
Figure 1 is a prior art route to fulvestrant;
FIG. 2 is a graph of the oxidative addition-reductive elimination cycle of the fulvestrant EAS addition reaction;
FIG. 3 is a simplified schematic diagram of the charge monitoring system apparatus of an embodiment of the present invention;
FIG. 4 is a schematic diagram of the charge monitoring system apparatus components of an embodiment of the present invention;
FIG. 5 is a reaction formula of an addition reaction of an embodiment of the present invention;
the device comprises a reaction device 10, a color detection module 20, a feeding template 30, a main controller 40, a glass reactor 11, an electric mechanical stirrer 12, a thermometer 13, an inert gas inlet pipeline 14, an inert gas outlet pipeline 15, a color detection probe 21, a color identification converter 22, a speed-regulating peristaltic pump 31, a material storage tank 32, a feeding pipeline 33 and a computer 41.
Detailed Description
The preferred embodiments of the present invention will be described below with reference to the accompanying drawings for clarity and understanding of technical contents. The present invention may be embodied in many different forms of embodiments and the scope of the invention is not limited to the embodiments set forth herein.
In the drawings, structurally identical elements are represented by like reference numerals, and structurally or functionally similar elements are represented by like reference numerals throughout the several views. The size and thickness of each component shown in the drawings are arbitrarily illustrated, and the present invention is not limited to the size and thickness of each component. The thickness of the components may be exaggerated where appropriate in the figures to improve clarity.
As shown in fig. 3, a charging monitoring system applied to fulvestrant real-time feedback comprises a reaction device 10, a color detection module 20, a charging template 30 and a main controller 40, wherein the main controller 40 controls the operation of the color detection module 20 and the charging module 30 through instructions.
As shown in fig. 4, the reaction apparatus 10 includes a glass reaction flask 11, an electromechanical stirrer 12, an alcohol thermometer 13, an inert gas inlet pipe 14 and an outlet pipe 15, the inert gas is nitrogen, the reaction needs to be controlled to be anhydrous and anaerobic, and the glass reactor is a closed apparatus except for an inert gas flowing apparatus.
The detection module 20 comprises a color detection probe 21 and a color identification converter 22 electrically connected with the color detection probe; the color detection probe 21 detects a color signal and transmits the color signal to the color recognition converter 22, and the color recognition converter 22 converts the color signal into digital information and transmits the digital information to the main controller 40.
The charging module 30 comprises a peristaltic pump 31 of the variable speed type, a hopper 32, a charging conduit 33. The holding tank is filled with a solution of the reaction starting material dienone in a solvent, tetrahydrofuran, which is usually also blanketed with an inert gas. The peristaltic pump 31 and the reservoir 32 are connected to the glass reactor 11 through the feed line 33, the peristaltic pump 31 is connected to the main controller 40, and the main controller 40 controls the feed rate of the peristaltic pump 31 through the received color numerical information. The main controller 40 is a computer 41 provided with a color comparison program.
The charging monitoring system is implemented by a reaction formula shown in fig. 5, and the specific method comprises the following steps:
1) a glass reaction flask 11 equipped with an alcohol thermometer 13, a color detection probe 21, and an electromechanical stirrer 12 was charged with nitrogen, a predetermined amount of 0.38M Grignard reagent 1950mL was added, the mixture was placed in a freezer with a cooling bath at-40 ℃ and the solution was cooled to-35 ℃ with stirring, and then 4.3g (0.043 mol) of cuprous chloride was added and stirred for 15 min.
2) Set the detection frequency on the main controller 40, turn on the peristaltic pump 31, program control the automatic addition of the dienone THF solution (172.5 g, dissolved in 810mL dry THF) for 4h, complete HPLC detection reaction, HPLC detection conditions: the mobile phase is acetonitrile: water =98:2, wavelength 220nm, 1.5mL/min, to a dienone proportion of less than 1%, add acetic acid THF solution (solution of 274g acetic acid and 170mL THF) and after addition warm to room temperature and stir for 8 h.
3) 1207.5mL of water is added into the reaction solution, 4.14g of antioxidant is added at 0 ℃, after stirring uniformly, THF is distilled off at 35 ℃ under reduced pressure, 517.5mL of water and 862.5mL of n-hexane are added, the solution is filtered by suction after being paved with diatomite, the filtrate is separated, the water layer is extracted once by n-hexane, the organic layers are combined, washed once by 690mL of 25% KCl solution, dried and evaporated to dryness at 35 ℃ under reduced pressure, 507.6g of EAS oily matter is obtained, the external standard yield is 94.6%, α: β =3.5: 1.
According to the artificial feeding mode, the external standard yield is usually 85-95%, the purity is 88-96%, the proportion of α: β in chiral configuration is 2.5-3.5: 1, wherein α configuration is the final medicinal configuration, the yield is usually 92-99%, the purity is 95-99%, and the proportion of α: β is 3.3-3.7: 1 by feeding through the feeding device, so that the yield and the target isomer ratio of the fulvestrant intermediate EAS obtained by applying the device are higher, the repeatability is better, the purity is higher, the artificial fatigue operation is avoided, and the labor cost is saved.
The foregoing detailed description of the preferred embodiments of the invention has been presented. It should be understood that numerous modifications and variations could be devised by those skilled in the art in light of the present teachings without departing from the inventive concepts. Therefore, the technical solutions available to those skilled in the art through logic analysis, reasoning and limited experiments based on the prior art according to the concept of the present invention should be within the scope of protection defined by the claims.
Claims (10)
1. A method for preparing a fulvestrant intermediate by using a charge monitoring system is characterized by comprising the following steps:
step 1, filling inert gas into a reactor with a temperature detector, a color detector and a stirrer, adding a Grignard reagent, putting the mixture into a refrigerator with a cold bath at-40 ℃, stirring the solution, cooling the solution to-35 ℃, adding cuprous chloride, and stirring;
step 2, starting a feeding monitoring system, setting detection frequency, starting a peristaltic pump, controlling the peristaltic pump to automatically add the dienone solution by a main controller through a program instruction, adding the dienone solution to the peristaltic pump, detecting the reaction by using HPLC, adding the acetic acid solution when the dienone proportion is less than 1%, and after the addition is finished, returning the temperature to the room temperature and stirring the mixture;
and 3, adding water into the reaction liquid at 0 ℃, adding an antioxidant, uniformly stirring, performing reduced pressure distillation to remove the reaction solvent, adding water and n-hexane, performing suction filtration, layering the filtrate, extracting the water layer once with n-hexane, combining the organic layers, washing once with a potassium chloride solution, drying, and performing reduced pressure distillation to obtain the fulvestrant EAS intermediate oily substance.
2. The method for preparing fulvestrant intermediates using a charge monitoring system of claim 1 wherein the main controller commands a peristaltic pump to automatically add the dienone solution by:
when the color of the reaction liquid is detected to be between light rose color and dark fresh meat color, the peristaltic pump feeds the materials at 100% of the set speed;
when the color of the reaction liquid is detected to be between the color of the dark fresh meat and the color of the tomato, the peristaltic pump feeds materials at 75% of the set speed;
when the color of the reaction liquid is detected to be between tomato red and orange red, a peristaltic pump feeds materials at 25% of a set speed;
when the color of the reaction liquid is detected to be between orange and red, the peristaltic pump stops feeding.
3. The method for preparing fulvestrant intermediates using a charge monitoring system of claim 1 wherein the main controller commands a peristaltic pump to automatically add the dienone solution by:
the main controller records the bandwidth of the color change of the reaction liquid through manual feeding operation reaction, records the lightest color point and the darkest color point, and linearly and uniformly adjusts the reaction speed according to the color of the reaction liquid in the subsequent feeding process of the reaction liquid;
when the detected reaction liquid is the lightest color point, the peristaltic pump feeds materials at 100% of the set speed;
when the color point of the reaction solution is the darkest, the peristaltic pump stops feeding.
4. The method of preparing a fulvestrant intermediate using a feed monitoring system of claim 1, wherein the reactor comprises a glass reactor, a stainless steel reactor, or an enamel reactor.
5. The method of preparing a fulvestrant intermediate using a charge monitoring system of claim 1 wherein the agitator is a magnetic agitator or an electromechanical agitator.
6. The method of preparing a fulvestrant intermediate using a feed monitoring system of claim 1 wherein the inert gas is nitrogen or argon.
7. The method of preparing a fulvestrant intermediate using a charge monitoring system of claim 1 wherein the temperature detector is an alcohol thermometer, a probe temperature detector or an infrared temperature detector.
8. A charge monitoring system using the method for preparing a fulvestrant intermediate according to claim 1, comprising a reaction device, a color detection module, a charge template, and a main controller, wherein the reaction device is connected to the detection module and the charge module, and the detection module and the charge module are connected to the main controller, and the main controller controls the operation of the detection module and the charge module by instructions;
the reaction device comprises a reactor, a stirrer, a temperature detector and inert gas inlet and outlet pipelines, and the reactor is a closed device except an inert gas flowing device;
the detection module comprises a color detection probe and a color recognition converter electrically connected with the color detection probe, the color detection probe detects a color signal and sends the color signal to the color recognition converter, and the color recognition converter converts the color signal into digital information and sends the digital information to the main controller;
the feeding module comprises a speed-regulating peristaltic pump and a feeding device, the peristaltic pump and the feeding device are connected with the reactor through a feeding pipe, the peristaltic pump is connected with a main controller, and the main controller controls the feeding speed of the peristaltic pump through received color digital information.
9. The charge monitoring system with real-time feedback for fulvestrant applications of claim 8, wherein the master controller is wired or wirelessly connected to the color recognition converter; the main controller is in wired or wireless connection with the peristaltic pump.
10. The charge monitoring system for real-time feedback of fulvestrant application of claim 8, wherein the master controller is a computer with a color comparison program or a cell phone with a color comparison app.
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