CN108794405B - Method for continuously preparing Olaparib intermediate by adopting micro-channel modular reaction device - Google Patents
Method for continuously preparing Olaparib intermediate by adopting micro-channel modular reaction device Download PDFInfo
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Abstract
The invention discloses a method for continuously preparing an olaparib intermediate by adopting a microchannel modular reaction device, which comprises the steps of reacting a dichloromethane solution of 3-hydroxyisobenzofuran-1 (3H) -ketone and a dichloromethane solution of dimethyl phosphite in a first microreactor, and separating liquid to obtain an effluent liquid of (3-oxo-1, 3-dihydroisobenzofuran-1-yl) dimethyl phosphate; then reacting with dichloromethane solution of 2-fluoro-5-formyl benzonitrile and dichloromethane solution of triethylamine in a second microreactor to generate reaction liquid of 2-fluoro-5- (3-oxo-3H-isobenzofuran-1-yl methylene) benzonitrile; and finally, reacting the reaction solution with a homogeneous mixed solution obtained by stirring an ethanol solution of sodium hydroxide and hydrazine hydrate in a third microreactor, and treating the effluent to obtain the intermediate 2-fluoro-5- [ (4-oxo-3, 4-dihydronaphthyridin-1-yl) methyl ] benzoic acid of the olaparib.
Description
Technical Field
The invention relates to a method for preparing an antitumor drug olaparib intermediate, in particular to a method for preparing 2-fluoro-5- [ (4-oxo-3, 4-dihydronaphthyridin-1-yl) methyl ] benzoic acid which is an important intermediate of olaparib by adopting a micro-channel modular reaction device in a continuous flow manner.
Background
Olaparib (Olaparib), the chemical name of which is 1- (cyclopropane formyl) -4- [5- [ (3, 4-dihydro-4-oxo-1-phthalazinyl) methyl ] -2-fluorobenzoyl ] piperazine, is a potent oral PARP inhibitor, which can promote tumor cell apoptosis by inhibiting tumor cell DNA damage repair and simultaneously enhance the curative effects of radiotherapy and alkylating agent and platinum drug chemotherapy. Olaparib is currently in clinical stage II and is mainly used for treating gene mutation cancer of breast cancer gene I or II (BRCA-1 or BRCA-2) (mainly existing in breast cancer, ovarian cancer and the like).
According to the report of domestic and foreign documents on the synthetic route of Olaparib, the following reactions are mainly carried out, 3-hydroxyisobenzofuran-1 (3H) -ketone and dimethyl phosphite are reacted to prepare a phosphorus Ylide reagent, and an important intermediate 2-fluoro-5- [ (4-oxo-3, 4-dihydronaphthyridin-1-yl) methyl ] benzoic acid is obtained through Wittig-Horner reaction, hydrolysis, cyclization and acidification; the cyclopropane carboxylic acid is subjected to acyl chlorination, condensation and protective group removal to obtain piperazine cyclopropyl ketone, and the 2-fluoro-5- [ (4-oxo-3, 4-dihydronaphthyridine-1-yl) methyl ] benzoic acid is subjected to acyl chlorination and amidation with the piperazine cyclopropyl ketone to obtain the target product olaparib. The traditional method for synthesizing olaparib has the defects of low yield, more impurities, difficulty in purification, incapability of realizing scale-up production and the like. So far, no application report of applying the microreactor to the synthesis of the antitumor drug is found.
Microreactor technology has great potential in current synthesis reactions. The micro-reactors have a fundamental characteristic that the chemical reaction is controlled in a space as small as possible, and the size order of the chemical reaction space is generally micron or even nanometer. Microreactors have a number of advantages over batch reactions, such as: the method has the advantages of extremely large specific surface area, small real-time on-line amount, continuous flow of fluid in the microreactor, almost no back mixing, high mass transfer and heat transfer efficiency, easy process control, less side reaction, easy industrial production and the like.
Disclosure of Invention
The purpose of the invention is as follows: aiming at the defects of low yield, more byproducts, difficult purification and the like in the existing synthesis and preparation process of antitumor drug Olaparib, the invention provides a method for continuously preparing an Olaparib intermediate by adopting a micro-channel modular reaction device, and the method has the advantages of simple and rapid operation, high yield, low production cost, good application prospect and industrial amplification production value.
The technical scheme is as follows: the method for continuously preparing the intermediate of the olaparib by adopting the micro-channel modular reaction device comprises the following steps:
step (1): pumping a dichloromethane solution of 3-hydroxyisobenzofuran-1 (3H) -ketone and a dichloromethane solution of dimethyl phosphite into a first mixing valve from a pump A and a pump B in a first-stage microchannel reaction device respectively, pumping into a first microreactor in the first-stage microchannel reaction device for reaction after fully mixing, and allowing effluent liquid to flow into a first separation device filled with water for extraction and liquid separation to obtain a reaction liquid containing (3-oxo-1, 3-dihydroisobenzofuran-1-yl) dimethyl phosphate (compound 1);
step (2): allowing the reaction liquid obtained in the step (1) to flow into a second mixing valve in a second section of continuous microchannel reaction device, pumping the dichloromethane solution of 2-fluoro-5-formylbenzonitrile and the dichloromethane solution of triethylamine into the second mixing valve from a pump C and a pump D in the second section of continuous microchannel reaction device respectively, and pumping into a second microreactor in the second section of continuous microchannel reaction device for reaction after fully mixing to obtain a reaction effluent containing 2-fluoro-5- (3-oxo-3H-isobenzofuran-1-ylmethylene) benzonitrile (compound 2);
and (3): pumping a homogeneous mixed solution obtained by stirring an ethanol solution of sodium hydroxide and hydrazine hydrate into a third mixing valve in a third-section continuous microchannel reaction device from a pump E in the third-section continuous microchannel reaction device, simultaneously pumping a reaction effluent liquid containing 2-fluoro-5- (3-oxo-3H-isobenzofuran-1-ylmethylene) benzonitrile obtained in the step (2) into the third mixing valve, fully mixing, pumping into a third microreactor in the third-section continuous microchannel reaction device for reaction to obtain 2-fluoro-5- [ (4-oxo-3, 4-dihydronaphthyridin-1-yl) methyl ] benzoic acid (compound 3), namely the olapanil intermediate.
In the step (1), the concentration of the dichloromethane solution of the 3-hydroxyisobenzofuran-1 (3H) -ketone is 0.4-1.2 mol/L, preferably 0.5-0.8 mol/L; the concentration of the methylene dichloride solution of the dimethyl phosphite is 1.0-7.2 mol/L, preferably 1.4-2.2 mol/L; the molar ratio of the 3-hydroxyisobenzofuran-1 (3H) -ketone to the dimethyl phosphite is 1: 2.5-6, and preferably 1: 2.8.
In the step (1), the flow rate of the pump A is 0.11-0.22 mL/min, preferably 0.15-0.2 mL/min, and the flow rate of the pump B is 0.018-0.035 mL/min, preferably 0.024-0.033 mL/min; the volume of the first microreactor is 5-50 mL, preferably 10-40 mL, the residence time of the reaction is 2.8-55 min, preferably 10-45 min, and the reaction temperature in the first microreactor is 90-120 ℃, preferably 100-120 ℃, and more preferably 100 ℃.
In the step (2), the flow rate of the reaction solution obtained in the step (1) is 0.51-2.76 mol/min, preferably 0.8-2.36 mol/min; the concentration of the dichloromethane solution of the 2-fluoro-5-formylbenzonitrile is 0.3-0.8 mol/L, preferably 0.44-0.75 mol/L; the concentration of the dichloromethane solution of the triethylamine is 0.15-2.72 mol/L, preferably 0.31-0.525 mol/L; the molar ratio of the 3-hydroxyisobenzofuran-1 (3H) -ketone to the 2-fluoro-5-formylbenzonitrile to the triethylamine is 1: 0.5-1.0: 0.3-1.25, preferably 1: 0.6: 0.4.
In the step (2), the flow rate of the pump C is 0.21-0.44 mL/min, preferably 0.22-0.42 mL/min; the flow rate of the pump D is 0.3-0.63 mL/min, preferably 0.36-0.578 mL/min; the volume of the second microreactor is 5-50 mL, preferably 10-40 mL; the residence time of the reaction is 3.5-60 min, preferably 10-45 min; the reaction temperature in the second microreactor is 0-20 ℃, and preferably 15 ℃.
In the step (3), the concentration of the ethanol solution of the sodium hydroxide is 1.58-4.21 mol/L, preferably 2.1 mol/L; the volume ratio of the ethanol to the hydrazine hydrate is 1: 0.257-0.628, preferably 1: 0.324; the temperature of the sodium hydroxide ethanol solution and hydrazine hydrate during stirring is 60-70 ℃, and preferably 70 ℃; the molar ratio of the 2-fluoro-5- (3-oxo-3H-isobenzofuran-1-yl methylene) benzonitrile to the sodium hydroxide is 1: 3-8, and the preferable ratio is 1: 4.78.
In the step (3), the reaction effluent of the third microreactor is subjected to post-treatment to obtain 2-fluoro-5- [ (4-oxo-3, 4-dihydronaphthyridin-1-yl) methyl ] benzoic acid (compound 3).
And the post-treatment comprises the steps of cooling the reaction effluent to room temperature, injecting 1.8-2.2 mol/L hydrochloric acid to adjust the pH value to 3.8-4.2, stirring, injecting water and ethyl acetate, extracting, separating, filtering, washing and drying. Preferably, the post-treatment comprises cooling the reaction effluent to room temperature, injecting 2mol/L hydrochloric acid to adjust the pH value to 4, stirring, injecting water and ethyl acetate, extracting, separating, filtering, washing and drying.
In the step (3), the flow rate of the pump E is 0.8-5.85 mL/min, preferably 1.2-2.68 mL/min; the flow rate of the reaction effluent containing the 2-fluoro-5- (3-oxo-3H-isobenzofuran-1-ylmethylene) benzonitrile obtained in the step (2) is 1.22-5.95 mL/min, preferably 1.56-3.14 mL/min, and the volume of the third microreactor is 5-50 mL, preferably 10-40 mL; the residence time of the reaction is 0.9-30 min, preferably 10-20 min; the reaction temperature in the third microreactor is 70-100 ℃, and preferably 70 ℃.
The microchannel modular reaction device comprises a first section of microchannel reaction device, a second section of continuous microchannel reaction device and a third section of continuous microchannel reaction device which are sequentially connected in series, wherein the first section of microchannel reaction device comprises a pump A, a pump B, a first mixing valve, a first microreactor and a first separation device, the pump A and the pump B are connected with the first mixing valve through a connecting pipe in a parallel connection mode, the first mixing valve, the first microreactor and the first separation device are connected with each other through the connecting pipe in a series connection mode, the second section of continuous microchannel reaction device comprises a pump C, a pump D, a second mixing valve and a second microreactor, the first separation device, the pump C and the pump D are connected with the second mixing valve through the connecting pipe in a parallel connection mode, the second mixing valve and the second microreactor are connected with each other through the connecting pipe in a series connection mode, and the third section of continuous microchannel reaction device comprises a pump E, The second micro-reactor and the pump E are connected with the third mixing valve through a connecting pipe in a parallel mode, and the third mixing valve, the third micro-reactor and the third receiving device are connected with each other through a connecting pipe in a series mode.
The device can be input into a micromixer and subsequent equipment by a precise and low-pulsation pump (such as an HPLC pump or an injection pump), so that materials can continuously pass through the microchannel modular reaction device and the residence time of the materials can be controlled. The raw material storage tank and the product collecting bottle can be respectively connected at the head and the tail according to requirements to realize continuous operation. The pump described in the present invention is preferably an HPLC pump; the models of the first microstructure mixer, the second microstructure mixer and the third microstructure mixer are T type, Y type and inverted Y type, and the Y type is preferred; the first, second and third microreactors are in the type of a channel reactor, a heart-shaped reactor, preferably a channel reactor;
the mixing valve in the microchannel reaction device can be a T-shaped mixing valve, a Y-shaped mixing valve, an inverted Y-shaped mixing valve and the like, and the Y-shaped mixing valve is preferred.
The diameter of the connecting pipe is 0.5-4 mm, the connecting pipe comprises a liquid inlet pipe, a connecting pipe between the mixing valve and the micro-reaction device and a liquid outlet pipe between the micro-reaction device and the receiving device, and the length of each section of the connecting pipe is 10-70 cm, preferably 10-40 cm; the diameters of the pipelines of the first, second and third microreactors are 0.5-4 mm, and preferably 0.5-2 mm; the material connecting pipe used in the present invention is controlled in the above preferable range, although the thin pipe diameter can effectively increase the specific surface area, it may cause the liquid flow pressure to rise, which may cause the problems of blockage, pipe burst, etc.
In the invention, after synthesis conditions are optimized and a microchannel device is added, the reaction is simple, the post-treatment is easy, the yield is relatively high, the improved process cost is low, the operation is simple and convenient, and the potential of pilot scale amplification is realized.
Has the advantages that:
(1) the invention optimizes the process on the known route for synthesizing the olaparib, and in the synthesis process of the (3-oxo-1, 3-dihydroisobenzofuran-1-yl) dimethyl phosphate (compound 1), the dimethyl phosphite and the 3-hydroxyisobenzofuran-1 (3H) -ketone react under the high temperature condition, and the optimum reaction temperature is determined to be 100 ℃ through investigation, so that the yield can be obviously improved to 85 percent.
(2) According to the invention, 2-fluoro-5- [ (4-oxo-3, 4-dihydronaphthyridin-1-yl) methyl ] benzoic acid is continuously prepared from 3-hydroxyisobenzofuran-1 (3H) -one by adopting a microchannel reaction device, and the product obtained in each step is directly put into the next step for reaction without purification to obtain the olaparib intermediate, so that the yield is not reduced, but the operation is greatly simplified, the consumption of the intermediate in each step is reduced, and the yield is improved.
(3) The whole process has short reaction time and simple and convenient post-treatment, can simplify the complex multistep synthesis process, realizes simple and convenient production of the olaparib intermediate 2-fluoro-5- [ (4-oxo-3, 4-dihydronaphthyridin-1-yl) methyl ] benzoic acid, and avoids the long time consumption and complex operation of the traditional process.
(4) The invention has the advantages of low toxicity and pollution, low production cost, good product quality, high profit, environmental protection, energy conservation and high efficiency, and has the potential of industrial amplification.
Drawings
FIG. 1 is a schematic diagram of the synthesis route of the microchannel reactor apparatus used in the present invention.
FIG. 2 shows the reaction equation of the present invention.
Detailed Description
The invention will be better understood from the following examples.
The microchannel reactor device described in the following examples, as shown in fig. 1, comprises a first-stage microchannel reactor device, a second-stage continuous microchannel reactor device and a third-stage continuous microchannel reactor device connected in series in sequence, wherein the first-stage microchannel reactor device comprises a pump a1, a pump B2, a first mixing valve 3, a first microreactor 4 and a first separation device 5; the second-stage continuous microchannel reaction device comprises a pump C6, a pump D7, a second mixing valve 8 and a second microreactor 9; the third-stage continuous micro-reaction channel device comprises a pump E10, a third mixing valve 11, a third microreactor 12 and a third receiving device 13. The pump a1 and the pump B2 are connected in parallel by a connecting tube and the first mixing valve 3, the first microreactor 4 and the first separating means 5 are connected in series by a connecting tube, the first separating means 5, the pump C6 and the pump D7 are connected in parallel by a connecting tube and the second mixing valve 8, the second mixing valve 8 and the second microreactor 9 are connected in series by a connecting tube, the second microreactor 9 and the pump E10 are connected in parallel by a connecting tube and the third mixing valve 11, the third microreactor 12 and the third receiving means 13 are connected in series by a connecting tube.
The reaction raw materials enter the micro-structure mixer through an HPLC pump or an injection pump and then enter the micro-reactor. The first, second and third micro-structure mixers are Y-shaped. The first micro reactor, the second micro reactor and the third micro reactor are channel reactors.
Example 1
(1) In a microchannel reactor apparatus, a solution of 3-hydroxyisobenzofuran-1 (3H) -one (0.033mol) in methylene chloride (50mL) and a solution of dimethyl phosphite (0.091mol) in methylene chloride (50mL) were pumped from pump A1, pump B2, to first mixing valve 3, pump A1 at a flow rate of 0.18mL/min and pump B2 at a flow rate of 0.026mL/min, respectively. After being fully mixed, the mixture enters a first microreactor 4, the volume of the first microreactor 4 is 40mL, and the reaction residence time is 25 min. The reaction temperature was 100 ℃, the reaction solution was collected in a first separation apparatus 5, the first separation apparatus 5 was a vessel containing water and dichloromethane, and the effluent of dimethyl (3-oxo-1, 3-dihydroisobenzofuran-1-yl) phosphate (compound 1) obtained after simple extraction, liquid separation and washing was found to have a yield of 85%.
(2) With the reaction liquid obtained in the step (1) flowing into the second mixing valve at a flow rate of 1.24mL/min, simultaneously pumping a dichloromethane solution (25mL) of 2-fluoro-5-formylbenzonitrile (0.02mol) and a dichloromethane solution (25mL) of triethylamine (0.014mol) from a pump C6 and a pump D7 in the second continuous microchannel reaction device to a second mixing valve 8 respectively, wherein the flow rate of the pump C6 is 0.22mL/min, the flow rate of the pump D7 is 0.36mL/min, after sufficient mixing, pumping the mixture to a second microreactor 9 in the second continuous microchannel reaction device for reaction, the volume of the second microreactor 9 is 40mL, the retention time is 20min, the heating temperature is 15 ℃, and a reaction effluent liquid of 2-fluoro-5- (3-oxo-3H-isobenzofuran-1-ylmethylene) benzonitrile (compound 2) is obtained, the yield was 95%.
(3) Stirring an ethanol solution (50mL) of sodium hydroxide (0.105mol) and hydrazine hydrate (17mL) at the stirring temperature of 70 ℃ to obtain a homogeneous mixed solution, and pumping the homogeneous mixed solution from a pump E10 into a third mixing valve 11, wherein the flow rate of the pump E11 is 2.2 mL/min; simultaneously, enabling the reaction effluent obtained in the step (2) to flow into a third mixing valve at a flow rate of 1.56mL/min after the 2-fluoro-5- (3-oxo-3H-isobenzofuran-1-ylmethylene) benzonitrile (0.022mol) flows into a third micro reactor in a third section of continuous micro-channel reaction device to be fully mixed, pumping the mixture into the third micro reactor for reaction at a reaction temperature of 70 ℃ for 10min, collecting the reaction effluent by a first receiving device 13, cooling the reaction effluent to room temperature, injecting 2mol/L diluted hydrochloric acid into the reaction effluent to adjust the pH value to 4, stirring the reaction effluent for 20min, injecting water (50mL) and ethyl acetate (50mL), extracting, separating, filtering, washing and drying to obtain the antitumor drug Olaparib intermediate 2-fluoro-5- [ (4-oxo-3, 4-dihydronaphthyridin-1-yl) methyl ] benzoic acid (compound 3), the yield thereof was found to be 91%.
Comparative example 1
The comparative example was carried out in a round bottom flask.
(1) 5.0g (0.033mol) of 3-hydroxyisobenzofuran-1 (3H) -one and 10.0g (0.091mol) of dimethyl phosphite are added into a three-necked flask, and the mixture is refluxed for 8 hours at 100 ℃ under the protection of nitrogen. After cooling to room temperature, 20mL of water and 50mL of dichloromethane were added to the reaction mixture, followed by liquid separation, and the dichloromethane layer was washed twice with 50mL of water, dried over anhydrous sodium sulfate, filtered, concentrated, and dried to obtain 4.1g of a white solid (Compound 1) with a yield of 50.1%.
(2) 5.0g (0.021mol) of Compound 1 and 3.0g (0.020mol) of 2-fluoro-5-formylbenzonitrile are dissolved in 50mL of anhydrous tetrahydrofuran, cooled to 0 ℃, 2.0mL (0.014mol) of triethylamine is slowly added dropwise, the temperature is kept at 15 ℃ or less, and after the addition is completed, the temperature is raised to room temperature for reaction for 18 hours. The solvent tetrahydrofuran was removed by distillation under reduced pressure, 25mL of water was added and stirred for 1h, followed by suction filtration and drying to obtain 4.5g of a pale yellow solid (compound 2) with a yield of 88.2%.
(3) 3.0g (0.011mol) of compound 2 are taken and added into 25mL of water, stirred at 20 ℃, added with 6mL (0.0525mol) of sodium hydroxide solution and heated to 90 ℃, and kept at the temperature for reaction for 1 h. The temperature is reduced to 70 ℃, 8.1mL (0.141mol) of hydrazine hydrate is added dropwise, and the reaction is kept at 70 ℃ for 18h after the addition. Cooling to room temperature, adjusting pH to 4 with 2mol/L dilute hydrochloric acid, stirring for 20min, filtering, washing filter cake with water and ethyl acetate in sequence, and drying to obtain pink solid (compound 3)2.5g with yield of 65.5%.
Comparative example 2
The procedure is the same as in example 1, except that:
in the step (1), the reaction temperature in the first microreactor is 80 ℃, and the effluent of (3-oxo-1, 3-dihydroisobenzofuran-1-yl) dimethyl phosphate (compound 1) is finally obtained, wherein the yield is 55%.
Example 2
The procedure is the same as in example 1, except that:
in the step (1), the reaction temperature in the first microreactor is 90 ℃, and the effluent of (3-oxo-1, 3-dihydroisobenzofuran-1-yl) dimethyl phosphate (compound 1) is finally obtained, wherein the yield is 76%.
Example 3
The procedure is the same as in example 1, except that:
in the step (1), the reaction temperature in the first microreactor is 120 ℃, and the effluent of (3-oxo-1, 3-dihydroisobenzofuran-1-yl) dimethyl phosphate (compound 1) is finally obtained, wherein the yield is 72%.
Example 4
The procedure is the same as in example 1, except that:
in the step (1), the concentration of a dichloromethane solution of 3-hydroxyisobenzofuran-1 (3H) -ketone is 0.4mol/L, and the concentration of a dichloromethane solution of dimethyl phosphite is 1.0 mol/L; the molar ratio of 3-hydroxyisobenzofuran-1 (3H) -one to dimethyl phosphite was 1: 2.5. The flow rate of the pump A is 0.11mL/min, and the flow rate of the pump B is 0.018 mL/min; the volume of the first microreactor is 5mL, and the reaction residence time is 55 min; the reaction temperature in the first microreactor was 120 ℃.
In the step (2), the concentration of the dichloromethane solution of the 2-fluoro-5-formylbenzonitrile is 0.3mol/L, and the concentration of the dichloromethane solution of the triethylamine is 0.20 mol/L. The molar ratio of 3-hydroxyisobenzofuran-1 (3H) -one, 2-fluoro-5-formylbenzonitrile and triethylamine is 1: 0.5: 0.3. The flow rate of the reaction solution obtained in the step (1) is 0.51mol/min, the flow rate of the pump C is 0.21mL/min, and the flow rate of the pump D is 0.3 mL/min; the volume of the second microreactor is 5mL, the residence time of the reaction is 58.1min, and the reaction temperature in the second microreactor is 0 ℃.
In the step (3), the concentration of the ethanol solution of the sodium hydroxide is 1.58 mol/L; the volume ratio of ethanol to hydrazine hydrate is 1: 0.257, and the temperature of the ethanol solution of sodium hydroxide and hydrazine hydrate is 60 ℃ when stirring; the molar ratio of 2-fluoro-5- (3-oxo-3H-isobenzofuran-1-ylmethylene) benzonitrile to sodium hydroxide was 1: 3. The flow rate of the pump E is 0.8mL/min, the flow rate of the reaction effluent containing the 2-fluoro-5- (3-oxo-3H-isobenzofuran-1-ylmethylene) benzonitrile obtained in the step (2) is 1.22mL/min, the volume of the third microreactor is 5mL, and the residence time of the reaction is 30 min; the reaction temperature in the third microreactor was 70 ℃.
Example 5
The procedure is the same as in example 1, except that:
in the step (1), the concentration of a dichloromethane solution of 3-hydroxyisobenzofuran-1 (3H) -ketone is 1.2mol/L, and the concentration of a dichloromethane solution of dimethyl phosphite is 7.2 mol/L; the molar ratio of 3-hydroxyisobenzofuran-1 (3H) -one to dimethyl phosphite was 1: 6. The flow rate of the pump A is 0.22mL/min, and the flow rate of the pump B is 0.035 mL/min; the volume of the first microreactor is 50mL, and the residence time of the reaction is 2.8 min; the reaction temperature in the first microreactor was 90 ℃.
In the step (2), the concentration of a dichloromethane solution of 2-fluoro-5-formylbenzonitrile is 0.8mol/L, and the concentration of a dichloromethane solution of triethylamine is 0.61 mol/L; the molar ratio of 3-hydroxyisobenzofuran-1 (3H) -one, 2-fluoro-5-formylbenzonitrile and triethylamine is 1: 1.0: 1.25. The flow rate of the reaction liquid obtained in the step (1) is 2.76mol/min, the flow rate of the pump C is 0.44mL/min, and the flow rate of the pump D is 0.43 mL/min; the volume of the second microreactor is 50mL, the residence time of the reaction is 3.5min, and the reaction temperature in the second microreactor is 20 ℃.
In the step (3), the concentration of the ethanol solution of the sodium hydroxide is 4.21 mol/L; the volume ratio of ethanol to hydrazine hydrate is 1: 0.628, and the temperature of the ethanol solution of sodium hydroxide and hydrazine hydrate is 70 ℃ when stirring; the molar ratio of 2-fluoro-5- (3-oxo-3H-isobenzofuran-1-ylmethylene) benzonitrile to sodium hydroxide was 1: 8. The flow rate of the pump E is 5.85mL/min, the flow rate of the reaction effluent containing the 2-fluoro-5- (3-oxo-3H-isobenzofuran-1-ylmethylene) benzonitrile obtained in the step (2) is 5.95mL/min, the volume of the third microreactor is 50mL, and the residence time of the reaction is 0.9 min; n; the reaction temperature in the third microreactor was 100 ℃.
Claims (6)
1. A method for continuously preparing an olaparib intermediate by adopting a microchannel modular reaction device is characterized by comprising the following steps:
step (1): pumping a dichloromethane solution of 3-hydroxyisobenzofuran-1 (3H) -ketone and a dichloromethane solution of dimethyl phosphite into a first mixing valve from a pump A and a pump B in a first section of microchannel reaction device respectively, pumping into a first microreactor in the first section of microchannel reaction device for reaction after fully mixing, and allowing effluent liquid to flow into a first separation device filled with water for extraction and liquid separation to obtain a reaction liquid containing (3-oxo-1, 3-dihydroisobenzofuran-1-yl) dimethyl phosphate; the flow rate of the pump A is 0.11-0.22 mL/min, and the flow rate of the pump B is 0.018-0.035 mL/min; the volume of the first microreactor is 5-50 mL, the reaction residence time is 2.8-55 min, and the reaction temperature in the first microreactor is 100 ℃;
step (2): along with the reaction liquid obtained in the step (1) flowing into a second mixing valve in a second section of continuous microchannel reaction device, pumping the dichloromethane solution of 2-fluoro-5-formylbenzonitrile and the dichloromethane solution of triethylamine into the second mixing valve from a pump C and a pump D in the second section of continuous microchannel reaction device respectively, and pumping into a second microreactor in the second section of continuous microchannel reaction device for reaction after fully mixing to obtain a reaction effluent containing 2-fluoro-5- (3-oxo-3H-isobenzofuran-1-ylmethylene) benzonitrile; the flow rate of the pump C is 0.21-0.44 mL/min, and the flow rate of the pump D is 0.3-0.63 mL/min; the volume of the second microreactor is 5-50 mL, the reaction residence time is 3.5-60 min, and the reaction temperature in the second microreactor is 0-20 ℃;
and (3): pumping a homogeneous mixed solution obtained by stirring an ethanol solution of sodium hydroxide and hydrazine hydrate into a third mixing valve in a third-section continuous microchannel reaction device from a pump E in the third-section continuous microchannel reaction device, simultaneously pumping a reaction effluent liquid containing 2-fluoro-5- (3-oxo-3H-isobenzofuran-1-ylmethylene) benzonitrile obtained in the step (2) into the third mixing valve, fully mixing, pumping into a third microreactor in the third-section continuous microchannel reaction device for reaction to obtain 2-fluoro-5- [ (4-oxo-3, 4-dihydronaphthyridin-1-yl) methyl ] benzoic acid, namely an olapanil intermediate; the flow rate of the pump E is 0.8-5.85 mL/min, the flow rate of the reaction effluent liquid containing the 2-fluoro-5- (3-oxo-3H-isobenzofuran-1-ylmethylene) benzonitrile obtained in the step (2) is 1.22-5.95 mL/min, the volume of the third microreactor is 5-50 mL, the residence time of the reaction is 0.9-30 min, and the reaction temperature in the third microreactor is 70-100 ℃.
2. The method according to claim 1, wherein in the step (1), the concentration of the dichloromethane solution of the 3-hydroxyisobenzofuran-1 (3H) -one is 0.4 to 1.2 mol/L; the concentration of the methylene dichloride solution of the dimethyl phosphite is 1.0-7.2 mol/L; the molar ratio of the 3-hydroxyisobenzofuran-1 (3H) -ketone to the dimethyl phosphite is 1 (2.5-6).
3. The method according to claim 1, wherein in the step (2), the flow rate of the reaction solution obtained in the step (1) is 0.51 to 2.76mol/min, the concentration of the dichloromethane solution of 2-fluoro-5-formylbenzonitrile is 0.3 to 0.8mol/L, the concentration of the dichloromethane solution of triethylamine is 0.15 to 2.72mol/L, and the molar ratio of 3-hydroxyisobenzofuran-1 (3H) -one, 2-fluoro-5-formylbenzonitrile and triethylamine is 1: (0.5-1.0): (0.3-1.25).
4. The method of claim 1, wherein in the step (3), the concentration of the ethanol solution of sodium hydroxide is 1.58-4.21 mol/L, and the volume ratio of ethanol to hydrazine hydrate is 1 (0.257-0.628); the temperature of the sodium hydroxide ethanol solution and hydrazine hydrate during stirring is 60-70 ℃; the molar ratio of 2-fluoro-5- (3-oxo-3H-isobenzofuran-1-ylmethylene) benzonitrile to sodium hydroxide was 1: (3-8); and the post-treatment comprises the steps of cooling the reaction effluent to room temperature, injecting 1.8-2.2 mol/L hydrochloric acid to adjust the pH value to 3.8-4.2, stirring, injecting water and ethyl acetate, extracting, separating, filtering, washing and drying.
5. The method of claim 1, wherein the microchannel modular reaction apparatus comprises a first-stage microchannel reaction apparatus, a second-stage continuous microchannel reaction apparatus and a third-stage continuous microchannel reaction apparatus connected in series in this order, the first-stage microchannel reaction apparatus comprising a pump A, a pump B, a first mixing valve, a first microreactor and a first separation apparatus, the pump A and the pump B being connected in parallel by a connecting pipe and the first mixing valve, the first microreactor and the first separation apparatus being connected in series by a connecting pipe, the second-stage continuous microchannel reaction apparatus comprising a pump C, a pump D, a second mixing valve, a second microreactor, the first separation apparatus, the pump C and the pump D being connected in parallel by a connecting pipe and the second mixing valve, the second mixing valve and the second microreactor being connected in series by a connecting pipe, the third-stage continuous microchannel reaction device comprises a pump E, a third mixing valve, a third microreactor and a third receiving device, wherein the second microreactor and the pump E are connected in parallel through a connecting pipe and the third mixing valve, the third microreactor and the third receiving device are connected in series through the connecting pipe.
6. The method of claim 5, wherein the connecting tube has a diameter of 0.5 to 4mm and a length of 10 to 70 cm; the diameters of the pipelines of the first, second and third microreactors are 0.5-4 mm.
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