CN117069618A - Method for preparing Abusitinib key intermediate by utilizing microchannel reactor - Google Patents
Method for preparing Abusitinib key intermediate by utilizing microchannel reactor Download PDFInfo
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- CN117069618A CN117069618A CN202211602307.XA CN202211602307A CN117069618A CN 117069618 A CN117069618 A CN 117069618A CN 202211602307 A CN202211602307 A CN 202211602307A CN 117069618 A CN117069618 A CN 117069618A
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- 238000000034 method Methods 0.000 title claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims abstract description 176
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims abstract description 120
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims abstract description 60
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims abstract description 44
- -1 acyl azide Chemical class 0.000 claims abstract description 24
- 235000019445 benzyl alcohol Nutrition 0.000 claims abstract description 20
- 238000005086 pumping Methods 0.000 claims abstract description 6
- 238000006969 Curtius rearrangement reaction Methods 0.000 claims abstract description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 105
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 47
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 34
- 239000000203 mixture Substances 0.000 claims description 28
- 238000002156 mixing Methods 0.000 claims description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 16
- 238000001035 drying Methods 0.000 claims description 15
- 230000008569 process Effects 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 10
- 150000001540 azides Chemical class 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 8
- 239000008096 xylene Substances 0.000 claims description 8
- CUCUIXICZOQVHK-UHFFFAOYSA-N 3-oxocyclobutane-1-carbonyl chloride Chemical compound ClC(=O)C1CC(=O)C1 CUCUIXICZOQVHK-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 2
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 230000008901 benefit Effects 0.000 abstract description 3
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 3
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 239000012074 organic phase Substances 0.000 description 39
- 230000001105 regulatory effect Effects 0.000 description 36
- 239000012295 chemical reaction liquid Substances 0.000 description 18
- PSAMWNBBHLUISE-UHFFFAOYSA-N benzyl n-(3-oxocyclobutyl)carbamate Chemical compound C=1C=CC=CC=1COC(=O)NC1CC(=O)C1 PSAMWNBBHLUISE-UHFFFAOYSA-N 0.000 description 13
- 239000005457 ice water Substances 0.000 description 12
- 239000007788 liquid Substances 0.000 description 12
- 238000010791 quenching Methods 0.000 description 12
- 230000000171 quenching effect Effects 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
- BCVZHHLJPZIBCC-UHFFFAOYSA-N 1-benzhydryl-3-methylazetidin-3-ol Chemical compound C1C(C)(O)CN1C(C=1C=CC=CC=1)C1=CC=CC=C1 BCVZHHLJPZIBCC-UHFFFAOYSA-N 0.000 description 6
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 6
- 238000005516 engineering process Methods 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 230000002194 synthesizing effect Effects 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 230000007547 defect Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000012948 isocyanate Substances 0.000 description 2
- 150000002513 isocyanates Chemical class 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- IENOFRJPUPTEMI-UHFFFAOYSA-N 3-oxocyclobutane-1-carboxylic acid Chemical compound OC(=O)C1CC(=O)C1 IENOFRJPUPTEMI-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 102000042838 JAK family Human genes 0.000 description 1
- 102000002295 Janus Kinase 1 Human genes 0.000 description 1
- 108010000837 Janus Kinase 1 Proteins 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- PUJDIJCNWFYVJX-UHFFFAOYSA-N benzyl carbamate Chemical compound NC(=O)OCC1=CC=CC=C1 PUJDIJCNWFYVJX-UHFFFAOYSA-N 0.000 description 1
- 239000003124 biologic agent Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000010924 continuous production Methods 0.000 description 1
- DFLRGCFWSRELEL-UHFFFAOYSA-N cyclobut-2-en-1-one Chemical compound O=C1CC=C1 DFLRGCFWSRELEL-UHFFFAOYSA-N 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000010587 phase diagram Methods 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 208000037851 severe atopic dermatitis Diseases 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C247/00—Compounds containing azido groups
- C07C247/20—Compounds containing azido groups with azido groups acylated by carboxylic acids
- C07C247/22—Compounds containing azido groups with azido groups acylated by carboxylic acids with the acylating carboxyl groups bound to hydrogen atoms, to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/08—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
Abstract
The application provides a method for preparing an Abiotinib intermediate by adopting a microchannel reactor, which comprises the steps of respectively dissolving 3-oxo-cyclobutaneacyl chloride and sodium azide, pumping the solution into the microchannel reactor I for acyl azide reaction, and continuously pumping the intermediate reaction solution into the microchannel reactor II for reaction with benzyl alcohol to obtain 3-oxo-cyclobutyl-benzyl carbamate. The application adopts the micro-channel reactor as core reaction equipment, realizes continuous acyl azide reaction and continuous Curtius rearrangement reaction, has the advantages of high yield and good quality, reduced reaction risk, high mass and heat transfer efficiency, safe and simple operation and the like, and is beneficial to the large-scale production and application of the intermediate.
Description
Technical Field
The application belongs to the field of medicine synthesis, and in particular relates to a method for synthesizing an acixitinib carbamate intermediate by adopting a continuous flow micro-channel reaction technology.
Background
The albuxinib (shown as formula 1) is a once-daily oral Janus kinase 1 (JAK 1) inhibitor, is suitable for adult patients with refractory or moderately severe atopic dermatitis which do not respond well to other systemic treatments (such as hormone or biological agents) or are unsuitable for the treatment, and is used at a dosage of 100mg or 200mg. The albociclib tablet was approved by the U.S. FDA at 2022, 1 and by NMPA at 2022, 4 and 11.
Wherein the compound 3-oxo-cyclobutyl carbamic acid benzyl ester ABTM-2 is a key intermediate for synthesizing the albuxitinib.
According to the synthesis method of the 3-oxo-cyclobutyl-benzyl carbamate reported in the prior literature, a conventional batch synthesis method is mainly adopted, wherein the main synthesis process route is as follows:
in this scheme, 3-oxocyclobutanecarboxylic acid (formula 2) is reacted with Diphenylphosphorylazide (DPPA) to form 3-oxocyclobutaneacyl azide intermediate (ABTM-1); the acyl azide (ABTM-1) is heated to remove the nitrogen rearrangement to produce 3-oxocyclobutylisocyanate (formula 3), and the isocyanate (formula 3) is captured by benzyl alcohol to produce benzyl 3-oxocyclobutylcarbamate (ABTM-2). The conventional batch synthesis of benzyl 3-oxo-cyclobutylcarbamate (ABTM-2) has obvious defects or shortcomings;
first, heating the acyl azide (ABTM-1) for a long period of time causes the generated 3-oxo-cyclobutyl-benzyl carbamate (ABTM-2) to be further decomposed into a series of byproducts such as benzyl carbamate (formula 4), cyclobuten-1-one (formula 5), urea compound (formula 6) and the like, and the generation of the byproducts further affects the yield and purity of intermediate products;
secondly, a large amount of nitrogen can be discharged when acyl azide (ABTM-1) is heated, potential huge potential safety hazards are large, and the reaction process is complex in operation and difficult to control;
third, the cost of the raw materials of the azide reaction, diphenylphosphorylazide (DPPA), is high, which affects the economy of the whole reaction route. These factors severely restrict the large-scale production and application of benzyl 3-oxo-cyclobutylcarbamate.
Thus, there is a strong need in the art for a process for synthesizing benzyl 3-oxocyclobutylcarbamate that allows for continuous azide reactions, improved yields and quality, reduced reaction risks, and easy and safe operation.
Disclosure of Invention
The application aims to solve the defects in the prior art and provides a method for synthesizing 3-oxo-cyclobutyl-benzyl carbamate based on a continuous flow micro-channel reaction technology. The method adopts the micro-channel reactor as core reaction equipment, realizes continuous acyl azide reaction and continuous Curtius rearrangement reaction, has the advantages of improving yield and product quality, reducing reaction risk, having high mass and heat transfer efficiency, being simple and safe to operate, and the like, and is beneficial to the large-scale production and application of the 3-oxo-cyclobutyl carbamic acid benzyl ester. Specifically, the application provides a method for preparing 3-oxo-cyclobutyl-benzyl carbamate by utilizing a microchannel reactor, wherein the synthetic route is as follows:
the method comprises the following steps:
step 1 preparation of ABTM-1
Adding 3-oxo-cyclobutaneacyl chloride into a solvent I, stirring and uniformly mixing to obtain a 3-oxo-cyclobutaneacyl chloride reaction solution, adding sodium azide into a solvent II, stirring and uniformly mixing to obtain a sodium azide reaction solution, pumping the 3-oxo-cyclobutaneacyl chloride reaction solution and the sodium azide reaction solution into a micro-channel reactor I respectively by adjusting proper flow rates to perform continuous acyl azide reaction and continuous Curtius rearrangement reaction, and after the reaction is finished, standing for a period of time to perform temperature precooling, and extracting and separating the solution to obtain a 3-oxo-cyclobutaneacyl azide intermediate solution ABTM-1;
step 2 preparation of ABTM-2
Mixing the 3-oxo-cyclobutaneacyl azide intermediate solution obtained in the step 1 with benzyl alcohol, pumping the mixture into a micro-channel reactor II at a proper flow rate for reaction, staying for a period of time for temperature preheating, and collecting the reaction solution of the 3-oxo-cyclobutyl-benzyl carbamate under a proper back pressure;
step 3-purification of the product
And (3) concentrating the reaction solution of the 3-oxo-cyclobutyl-benzyl carbamate obtained in the step (2) to be dry, recrystallizing, filtering, washing and drying to obtain a white solid of the 3-oxo-cyclobutyl-benzyl carbamate.
In some embodiments, the molar ratio of 3-oxocyclobutanecarbonyl chloride to sodium azide in step 1 is 1 (1-5), preferably 1: (1-2);
in some embodiments, the solvent I in step 1 is selected from one or more of acetone, toluene, xylene, and methyl tert-butyl ether, preferably one or more of toluene, xylene, methyl tert-butyl ether.
In some embodiments, the solvent II in step 1 is selected from one or more of water, ethanol, dimethylsulfoxide, and N, N-dimethylformamide, preferably one or more of water, ethanol.
In one or more embodiments, the concentration of the 3-oxocyclobutanecarbonyl chloride solution in step 1 is from 1.0 to 20mol/L, preferably from 1.0 to 4.0mol/L, and the concentration of the sodium azide solution in step 1 is from 1.0 to 20mol/L, preferably from 3.0 to 7.0mol/L.
In one or more embodiments, the reaction temperature in step 1 is from 0 to 50 ℃, preferably from 0 to 30 ℃, more preferably from 0 to 15 ℃.
In one or more embodiments, the reaction residence time in step 1 is from 2 to 30 minutes, preferably from 2 to 10 minutes, more preferably from 4 to 8 minutes.
In one or more embodiments, the extract in step 1 is selected from one or more of acetone, toluene, xylene, and methyl tert-butyl ether, preferably one or more of toluene, xylene, methyl tert-butyl ether. In one or more embodiments, the flow rate of the 3-oxo-cyclobutanecarbonyl chloride reaction solution in the step 1 is controlled to be 5-40mL/min, preferably 7-35mL/min, and the flow rate of the sodium azide reaction solution is controlled to be 5-40mL/min, preferably 7-35mL/min.
In one or more embodiments, the molar ratio of 3-oxocyclobutaneacyl azide intermediate to benzyl alcohol in step 2 is from 1 (1) to 3.
In one or more embodiments, the reaction temperature in step 2 is 100 to 200 ℃, preferably 130 to 150 ℃.
In one or more embodiments, the reaction back pressure in step 2 is from 0.1 to 2MPa, preferably from 0.1 to 1.1MPa.
In one or more embodiments, the reaction residence time in step 2 is from 2 to 30 minutes, preferably from 2 to 10 minutes, more preferably from 5 to 10 minutes.
In one or more embodiments, the concentration of benzyl alcohol in step 2 is 0.1-5.0mol/L, and the flow rate in step 2 is controlled to be 1-10mL/min, preferably 3-6mL/min.
In one or more embodiments, the microchannel reactor I in step 1 and the channel reactor II in step 2 are pipelined microreactors or chip microreactors.
In one or more embodiments, the recrystallization solvent in step 3 is selected from ethanol/n-hexane, wherein the volume ratio of ethanol to n-hexane is 1: (1-10), preferably 1: (1-5).
Drawings
FIG. 1 is a schematic diagram of a microchannel reaction system according to an embodiment of the present application.
FIG. 2 is a graph showing the results of the liquid phase of example 1 of the present application.
FIG. 3 is a graph showing the results of comparative example 1 of the present application.
Advantageous effects
1. The application adopts the micro-channel reaction technology to continuously synthesize the 3-oxo-cyclobutyl-benzyl carbamate, can effectively avoid the transition isocyanate from further reacting with other raw materials to generate various amide byproducts, and only needs conventional recrystallization for the post-reaction treatment, thus compared with the traditional batch reaction kettle, the application can effectively improve the reaction yield and the product quality.
2. The application synthesizes the 3-oxo-cyclobutyl-benzyl carbamate by adopting a continuous flow micro-channel reaction technology, and can effectively avoid the use of diphenyl phosphoryl azide (DPPA). Avoid heating for a long time to release nitrogen gas and bring potential hidden trouble to safe production.
Detailed Description
The application will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present application and are not intended to limit the scope of the present application. Furthermore, it should be understood that various changes and modifications can be made by one skilled in the art after reading the teachings of the present application, and such equivalents are intended to fall within the scope of the application as defined in the appended claims. The methods, apparatus and materials used in the examples are those conventional in the art unless otherwise indicated. The starting compounds in the examples are all commercially available.
Example 1
3-oxocyclobutaneacyl chloride (23.2 g,1.00 eq.) was added to 48ml toluene and stirred to mix well to obtain a 3-oxocyclobutaneacyl chloride reaction solution; sodium azide (20.0 g,1.75 eq.) was added to 68ml pure water and stirred and mixed to obtain sodium azide reaction solution; the flow rate of the 3-oxo-cyclobutaneacyl chloride reaction solution is regulated to be 14ml/min, the flow rate of the sodium azide reaction solution is regulated to be 17ml/min, the sodium azide reaction solution is input into a microchannel reactor I for reaction, the residence time is 4min, the temperature is 10+/-5 ℃ for precooling, the reaction is fed, and the discharged reaction solution is discharged into 200ml of ice water for quenching. The above liquid was extracted with toluene (50 mL. Times.3 times), and the organic phase was separated.
And (3) drying the organic phase, adding benzyl alcohol (20.8 g,1.10 eq.) into the organic phase, uniformly mixing, regulating the flow rate to 3.0ml/min, inputting the mixture into a micro-channel reactor II for reaction, keeping the residence time to 5min, preheating the mixture at 130+/-5 ℃, carrying out back pressure to 0.5-0.7MPa, and collecting discharged reaction liquid.
The obtained reaction solution was concentrated to dryness, recrystallized by adding ethanol/n-hexane (20 ml/80 ml), filtered and dried under vacuum at 50℃to obtain 31.5g of benzyl 3-oxocyclobutylcarbamate as white, purity 99.10% and yield 82%.
Example 2
Changing the temperature in the step (1) to 20+/-5 DEG C
3-oxocyclobutaneacyl chloride (23.2 g,1.00 eq.) was added to 48ml toluene and stirred to mix well to obtain a 3-oxocyclobutaneacyl chloride reaction solution; sodium azide (20.0 g,1.75 eq.) was added to 68ml pure water and stirred and mixed to obtain sodium azide reaction solution; the flow rate of the 3-oxo-cyclobutaneacyl chloride reaction solution is regulated to be 14ml/min, the flow rate of the sodium azide reaction solution is regulated to be 17ml/min, the sodium azide reaction solution is input into a microchannel reactor I for reaction, the residence time is 4min, the temperature is 20+/-5 ℃ for precooling, the reaction is fed, and the discharged reaction solution is discharged into 200ml of ice water for quenching. The above liquid was extracted with toluene (50 mL. Times.3 times), and the organic phase was separated.
And (3) drying the organic phase, adding benzyl alcohol (20.8 g,1.10 eq.) into the organic phase, uniformly mixing, regulating the flow rate to 3.0ml/min, inputting the mixture into a micro-channel reactor II for reaction, keeping the residence time to 5min, preheating the mixture at 130+/-5 ℃, carrying out back pressure to 0.5-0.7MPa, and collecting discharged reaction liquid.
The obtained reaction solution was concentrated to dryness, recrystallized by adding ethanol/n-hexane (20 ml/80 ml), filtered and dried under vacuum at 50℃to obtain 28.8g of white 3-oxo-cyclobutyl-carbamic acid benzyl ester with a purity of 98.87% and a yield of 75%.
Example 3
Changing the temperature in the step (1) to 0-5 DEG C
3-oxocyclobutaneacyl chloride (23.2 g,1.00 eq.) was added to 48ml toluene and stirred to mix well to obtain a 3-oxocyclobutaneacyl chloride reaction solution; sodium azide (20.0 g,1.75 eq.) was added to 68ml pure water and stirred and mixed to obtain sodium azide reaction solution; the flow rate of the 3-oxo-cyclobutaneacyl chloride reaction solution is regulated to be 14ml/min, the flow rate of the sodium azide reaction solution is regulated to be 17ml/min, the sodium azide reaction solution is input into a microchannel reactor I for reaction, the residence time is 4min, the temperature is 0+/-5 ℃ for precooling, the reaction is fed, and the discharged reaction solution is discharged into 200ml of ice water for quenching. The above liquid was extracted with toluene (50 mL. Times.3 times), and the organic phase was separated.
And (3) drying the organic phase, adding benzyl alcohol (20.8 g,1.10 eq.) into the organic phase, uniformly mixing, regulating the flow rate to 3.0ml/min, inputting the mixture into a micro-channel reactor II for reaction, keeping the residence time to 5min, preheating the mixture at 130+/-5 ℃, carrying out back pressure to 0.5-0.7MPa, and collecting discharged reaction liquid.
The obtained reaction solution was concentrated to dryness, recrystallized by adding ethanol/n-hexane (20 ml/80 ml), filtered and dried under vacuum at 50℃to obtain 31.5g of white 3-oxo-cyclobutyl-carbamic acid benzyl ester with a purity of 99.07% and a yield of 82%.
Example 4
Changing the residence time in the step (1) to 8min
3-oxocyclobutaneacyl chloride (23.2 g,1.00 eq.) was added to 48ml toluene and stirred to mix well to obtain a 3-oxocyclobutaneacyl chloride reaction solution; sodium azide (20.0 g,1.75 eq.) was added to 68ml pure water and stirred and mixed to obtain sodium azide reaction solution; 3-oxo-cyclobutaneacyl chloride reaction liquid flow rate is regulated to 7.0ml/min, sodium azide reaction liquid flow rate is regulated to 8.5ml/min, the mixture is input into a micro-channel reactor I for reaction, residence time is 8min, precooling is carried out at the temperature of 10+/-5 ℃, feeding reaction is carried out, and discharged reaction liquid is discharged into 200ml ice water for quenching. The above liquid was extracted with toluene (50 mL. Times.3 times), and the organic phase was separated.
And (3) drying the organic phase, adding benzyl alcohol (20.8 g,1.10 eq.) into the organic phase, uniformly mixing, regulating the flow rate to 3.0ml/min, inputting the mixture into a micro-channel reactor II for reaction, keeping the residence time to 5min, preheating the mixture at 130+/-5 ℃, carrying out back pressure to 0.5-0.7MPa, and collecting discharged reaction liquid.
The obtained reaction solution was concentrated to dryness, recrystallized by adding ethanol/n-hexane (20 ml/80 ml), filtered and dried under vacuum at 50℃to obtain 31.0g of white 3-oxo-cyclobutyl-carbamic acid benzyl ester with a purity of 98.90% and a yield of 81%.
Example 5
Changing the residence time in the step (1) to 2min
3-oxocyclobutaneacyl chloride (23.2 g,1.00 eq.) was added to 48ml toluene and stirred to mix well to obtain a 3-oxocyclobutaneacyl chloride reaction solution; sodium azide (20.0 g,1.75 eq.) was added to 68ml pure water and stirred and mixed to obtain sodium azide reaction solution; 3-oxo-cyclobutaneacyl chloride reaction liquid flow rate is regulated to 28ml/min, sodium azide reaction liquid flow rate is regulated to 34ml/min, the mixture is input into a microchannel reactor I for reaction, residence time is 2min, precooling is carried out at 10+/-5 ℃, feeding reaction is carried out, and discharged reaction liquid is discharged into 200ml of ice water for quenching. The above liquid was extracted with toluene (50 mL. Times.3 times), and the organic phase was separated.
And (3) drying the organic phase, adding benzyl alcohol (20.8 g,1.10 eq.) into the organic phase, uniformly mixing, regulating the flow rate to 3.0ml/min, inputting the mixture into a micro-channel reactor II for reaction, keeping the residence time to 5min, preheating the mixture at 130+/-5 ℃, carrying out back pressure to 0.5-0.7MPa, and collecting discharged reaction liquid.
The obtained reaction solution was concentrated to dryness, recrystallized by adding ethanol/n-hexane (20 ml/80 ml), filtered and dried under vacuum at 50℃to obtain 28.0g of white 3-oxo-cyclobutyl-carbamic acid benzyl ester with a purity of 98.74% and a yield of 73%.
Example 6
Changing the temperature in the step (2) to 110+/-5 DEG C
3-oxocyclobutaneacyl chloride (23.2 g,1.00 eq.) was added to 48ml toluene and stirred to mix well to obtain a 3-oxocyclobutaneacyl chloride reaction solution; sodium azide (20.0 g,1.75 eq.) was added to 68ml pure water and stirred and mixed to obtain sodium azide reaction solution; the flow rate of the 3-oxo-cyclobutaneacyl chloride reaction solution is regulated to be 14ml/min, the flow rate of the sodium azide reaction solution is regulated to be 17ml/min, the sodium azide reaction solution is input into a microchannel reactor I for reaction, the residence time is 4min, the temperature is 10+/-5 ℃ for precooling, the reaction is fed, and the discharged reaction solution is discharged into 200ml of ice water for quenching. The above liquid was extracted with toluene (50 mL. Times.3 times), and the organic phase was separated.
And (3) drying the organic phase, adding benzyl alcohol (20.8 g,1.10 eq.) into the organic phase, uniformly mixing, regulating the flow rate to 3.0ml/min, inputting the mixture into a micro-channel reactor II for reaction, keeping the residence time to 5min, preheating the mixture at 110+/-5 ℃, carrying out back pressure to 0.5-0.7MPa, and collecting discharged reaction liquid.
The resulting reaction solution was concentrated to dryness, recrystallized by adding ethanol/n-hexane (20 ml/80 ml), filtered and dried under vacuum at 50℃to give 29.2g of white 3-oxocyclobutyl carbamic acid benzyl ester with a purity of 98.80% and a yield of 76%.
Example 7
Changing the temperature in the step (2) to 150+/-5 DEG C
3-oxocyclobutaneacyl chloride (23.2 g,1.00 eq.) was added to 48ml toluene and stirred to mix well to obtain a 3-oxocyclobutaneacyl chloride reaction solution; sodium azide (20.0 g,1.75 eq.) was added to 68ml pure water and stirred and mixed to obtain sodium azide reaction solution; the flow rate of the 3-oxo-cyclobutaneacyl chloride reaction solution is regulated to be 14ml/min, the flow rate of the sodium azide reaction solution is regulated to be 17ml/min, the sodium azide reaction solution is input into a microchannel reactor I for reaction, the residence time is 4min, the temperature is 10+/-5 ℃ for precooling, the reaction is fed, and the discharged reaction solution is discharged into 200ml of ice water for quenching. The above liquid was extracted with toluene (50 mL. Times.3 times), and the organic phase was separated.
And (3) drying the organic phase, adding benzyl alcohol (20.8 g,1.10 eq.) into the organic phase, uniformly mixing, regulating the flow rate to 3.0ml/min, inputting the mixture into a micro-channel reactor II for reaction, keeping the residence time to 5min, preheating the mixture at 150+/-5 ℃, carrying out back pressure to 0.5-0.7MPa, and collecting discharged reaction liquid.
The obtained reaction solution was concentrated to dryness, recrystallized by adding ethanol/n-hexane (20 ml/80 ml), filtered and dried under vacuum at 50℃to obtain 31.3g of white 3-oxo-cyclobutyl-carbamic acid benzyl ester with a purity of 99.01% and a yield of 81%.
Example 8
Changing the residence time in the step (2) to 2.5min
3-oxocyclobutaneacyl chloride (23.2 g,1.00 eq.) was added to 48ml toluene and stirred to mix well to obtain a 3-oxocyclobutaneacyl chloride reaction solution; sodium azide (20.0 g,1.75 eq.) was added to 68ml pure water and stirred and mixed to obtain sodium azide reaction solution; the flow rate of the 3-oxo-cyclobutaneacyl chloride reaction solution is regulated to be 14ml/min, the flow rate of the sodium azide reaction solution is regulated to be 17ml/min, the sodium azide reaction solution is input into a microchannel reactor I for reaction, the residence time is 4min, the temperature is 10+/-5 ℃ for precooling, the reaction is fed, and the discharged reaction solution is discharged into 200ml of ice water for quenching. The above liquid was extracted with toluene (50 mL. Times.3 times), and the organic phase was separated.
And (3) drying the organic phase, adding benzyl alcohol (20.8 g,1.10 eq.) into the organic phase, uniformly mixing, regulating the flow rate to be 6.0ml/min, inputting the mixture into a micro-channel reactor II for reaction, keeping the residence time to be 2.5min, preheating the mixture at 130+/-5 ℃ and the back pressure to be 0.5-0.7MPa, and collecting discharged reaction liquid.
The obtained reaction solution was concentrated to dryness, recrystallized by adding ethanol/n-hexane (20 ml/80 ml), filtered and dried under vacuum at 50℃to obtain 23.4g of white 3-oxo-cyclobutyl-carbamic acid benzyl ester with a purity of 97.90% and a yield of 61%.
Example 9
Changing the residence time in the step (2) to 10min
3-oxocyclobutaneacyl chloride (23.2 g,1.00 eq.) was added to 48ml toluene and stirred to mix well to obtain a 3-oxocyclobutaneacyl chloride reaction solution; sodium azide (20.0 g,1.75 eq.) was added to 68ml pure water and stirred and mixed to obtain sodium azide reaction solution; the flow rate of the 3-oxo-cyclobutaneacyl chloride reaction solution is regulated to be 14ml/min, the flow rate of the sodium azide reaction solution is regulated to be 17ml/min, the sodium azide reaction solution is input into a microchannel reactor I for reaction, the residence time is 4min, the temperature is 10+/-5 ℃ for precooling, the reaction is fed, and the discharged reaction solution is discharged into 200ml of ice water for quenching. The above liquid was extracted with toluene (50 mL. Times.3 times), and the organic phase was separated.
And (3) drying the organic phase, adding benzyl alcohol (20.8 g,1.10 eq.) into the organic phase, uniformly mixing, regulating the flow rate to be 1.5ml/min, inputting the mixture into a micro-channel reactor II for reaction, keeping the residence time to be 10min, preheating the mixture at 130+/-5 ℃, carrying out back pressure to be 0.5-0.7MPa, and collecting discharged reaction liquid.
The obtained reaction solution was concentrated to dryness, recrystallized by adding ethanol/n-hexane (20 ml/80 ml), filtered and dried under vacuum at 50℃to obtain 31.1g of white 3-oxo-cyclobutyl-carbamic acid benzyl ester with a purity of 98.96% and a yield of 81%.
Example 10
Changing the back pressure in the step (2) to 0.1-0.4MPa
3-oxocyclobutaneacyl chloride (23.2 g,1.00 eq.) was added to 48ml toluene and stirred to mix well to obtain a 3-oxocyclobutaneacyl chloride reaction solution; sodium azide (20.0 g,1.75 eq.) was added to 68ml pure water and stirred and mixed to obtain sodium azide reaction solution; the flow rate of the 3-oxo-cyclobutaneacyl chloride reaction solution is regulated to be 14ml/min, the flow rate of the sodium azide reaction solution is regulated to be 17ml/min, the sodium azide reaction solution is input into a microchannel reactor I for reaction, the residence time is 4min, the temperature is 10+/-5 ℃ for precooling, the reaction is fed, and the discharged reaction solution is discharged into 200ml of ice water for quenching. The above liquid was extracted with toluene (50 mL. Times.3 times), and the organic phase was separated.
And (3) drying the organic phase, adding benzyl alcohol (20.8 g,1.10 eq.) into the organic phase, uniformly mixing, regulating the flow rate to 3.0ml/min, inputting the mixture into a micro-channel reactor II for reaction, keeping the residence time to 5min, preheating the mixture at 130+/-5 ℃, carrying out back pressure to 0.1-0.4MPa, and collecting discharged reaction liquid.
The obtained reaction solution was concentrated to dryness, recrystallized by adding ethanol/n-hexane (20 ml/80 ml), filtered and dried under vacuum at 50℃to obtain 30.0g of white 3-oxo-cyclobutyl-carbamic acid benzyl ester with a purity of 98.89% and a yield of 78%.
Example 11
Changing the back pressure in the step (2) to 0.8-1.1MPa
3-oxocyclobutaneacyl chloride (23.2 g,1.00 eq.) was added to 48ml toluene and stirred to mix well to obtain a 3-oxocyclobutaneacyl chloride reaction solution; sodium azide (20.0 g,1.75 eq.) was added to 68ml pure water and stirred and mixed to obtain sodium azide reaction solution; the flow rate of the 3-oxo-cyclobutaneacyl chloride reaction solution is regulated to be 14ml/min, the flow rate of the sodium azide reaction solution is regulated to be 17ml/min, the sodium azide reaction solution is input into a microchannel reactor I for reaction, the residence time is 4min, the temperature is 10+/-5 ℃ for precooling, the reaction is fed, and the discharged reaction solution is discharged into 200ml of ice water for quenching. The above liquid was extracted with toluene (50 mL. Times.3 times), and the organic phase was separated.
And (3) drying the organic phase, adding benzyl alcohol (20.8 g,1.10 eq.) into the organic phase, uniformly mixing, regulating the flow rate to 3.0ml/min, inputting the mixture into a micro-channel reactor II for reaction, keeping the residence time to 5min, preheating the mixture at 130+/-5 ℃, carrying out back pressure to 0.8-1.1MPa, and collecting discharged reaction liquid.
The obtained reaction solution was concentrated to dryness, recrystallized by adding ethanol/n-hexane (20 ml/80 ml), filtered and dried under vacuum at 50℃to obtain 31.4g of white 3-oxo-cyclobutyl-carbamic acid benzyl ester with a purity of 99.04% and a yield of 82%.
Example 12
The equivalent of benzyl alcohol in the step (2) was changed to 1.50eq.
3-oxocyclobutaneacyl chloride (23.2 g,1.00 eq.) was added to 48ml toluene and stirred to mix well to obtain a 3-oxocyclobutaneacyl chloride reaction solution; sodium azide (20.0 g,1.75 eq.) was added to 68ml pure water and stirred and mixed to obtain sodium azide reaction solution; the flow rate of the 3-oxo-cyclobutaneacyl chloride reaction solution is regulated to be 14ml/min, the flow rate of the sodium azide reaction solution is regulated to be 17ml/min, the sodium azide reaction solution is input into a microchannel reactor I for reaction, the residence time is 4min, the temperature is 10+/-5 ℃ for precooling, the reaction is fed, and the discharged reaction solution is discharged into 200ml of ice water for quenching. The above liquid was extracted with toluene (50 mL. Times.3 times), and the organic phase was separated.
And (3) drying the organic phase, adding benzyl alcohol (28.4 g,1.50 eq.) into the organic phase, uniformly mixing, regulating the flow rate to 3.0ml/min, inputting the mixture into a micro-channel reactor II for reaction, keeping the residence time to 5min, preheating the mixture at 130+/-5 ℃, carrying out back pressure to 0.5-0.7MPa, and collecting discharged reaction liquid.
The resulting reaction solution was concentrated to dryness, recrystallized by adding ethanol/n-hexane (20 ml/80 ml), filtered, and dried under vacuum at 50℃to give 27.7g of white 3-oxocyclobutyl carbamic acid benzyl ester with a purity of 98.69% and a yield of 72%
Comparative example 1-use of a conventional batch reaction
68ml of pure water and sodium azide (20.0 g,1.75 eq.) were added to the reaction flask, stirring was turned on, the solution was clear, and the internal temperature was adjusted to-10-0 ℃; dropwise adding a toluene solution of 3-oxo-cyclobutaneacyl chloride (23.2 g,1.00 eq.) and keeping the internal temperature at-10-0 ℃ for reaction for 1.0-1.5h; extracting twice with 60ml toluene, mixing the organic phases, adding anhydrous sodium sulfate for drying, and collecting the organic phases;
80ml toluene and benzyl alcohol (19.0 g,1.10 eq.) are added to another reaction flask, stirring is started, the internal temperature is adjusted to 95-105 ℃, the collected organic phase is slowly added dropwise to the reaction flask (release of nitrogen is more intense), and the reaction is continued for 5-7h after the addition; the reaction solution was concentrated to dryness under reduced pressure, recrystallized by adding ethanol/n-hexane (20 ml/80 ml), filtered, and dried under vacuum at 50℃to give 22.3g of benzyl 3-oxocyclobutylcarbamate, purity 93.82%, yield 58%.
Experimental result analysis-compared with the traditional intermittent reaction, the continuous synthesis of the 3-oxo-cyclobutyl-benzyl carbamate by adopting the flow micro-channel reaction technology can obviously improve the reaction safety and the reaction efficiency, further improve the product yield and quality and bring great economic benefit to continuous production of enterprises as shown by the results of the examples and the comparative examples and the liquid phase diagram.
The foregoing description is only illustrative of the present application and is not intended to limit the scope of the application, and all equivalent structures or equivalent processes or direct or indirect application in other related technical fields are included in the scope of the present application.
Claims (13)
1. A process for the continuous preparation of a key intermediate of albuxinib using a microchannel reactor, the process comprising the steps of:
step 1 preparation of ABTM-1
Adding 3-oxo-cyclobutaneacyl chloride into a solvent I, stirring and uniformly mixing to obtain a 3-oxo-cyclobutaneacyl chloride reaction solution, adding sodium azide into a solvent II, stirring and uniformly mixing to obtain a sodium azide reaction solution, pumping the 3-oxo-cyclobutaneacyl chloride reaction solution and the sodium azide reaction solution into a micro-channel reactor I respectively by adjusting proper flow rates to perform continuous acyl azide reaction and continuous Curtius rearrangement reaction, and after the reaction is finished, standing for a period of time to perform temperature precooling, and extracting and separating the solution to obtain a 3-oxo-cyclobutaneacyl azide intermediate solution ABTM-1;
step 2 preparation of ABTM-2
Mixing the 3-oxo-cyclobutaneacyl azide intermediate solution obtained in the step 1 with benzyl alcohol, pumping the mixture into a micro-channel reactor II at a proper flow rate for reaction, staying for a period of time for temperature preheating, and collecting the reaction solution of the 3-oxo-cyclobutyl-benzyl carbamate under a proper back pressure;
step 3-purification of the product
And (3) concentrating the reaction solution of the 3-oxo-cyclobutyl-benzyl carbamate obtained in the step (2) to dryness, recrystallizing, filtering, washing and drying to obtain a 3-oxo-cyclobutyl-benzyl carbamate solid.
2. The method according to claim 1, wherein the molar ratio of 3-oxocyclobutanecarbonyl chloride to sodium azide in step 1 is 1 (1-5), preferably 1: (1-2).
3. The process according to claim 1, wherein in step 1 the solvent I is selected from one or more of acetone, toluene, xylene and methyl tert-butyl ether, preferably one or more of toluene, xylene, methyl tert-butyl ether; the solvent II in the step 1 is selected from one or more of water, ethanol, dimethyl sulfoxide and N, N-dimethylformamide, preferably one or more of water and ethanol.
4. The process according to claim 1, wherein the concentration of the 3-oxocyclobutanecarbonyl chloride solution in step 1 is from 1.0 to 20mol/L, preferably from 1.0 to 4.0mol/L; the concentration of the sodium azide solution is 1.0 to 20mol/L, preferably 3.0 to 7.0mol/L.
5. The process according to claim 1, wherein the reaction temperature in step 1 is 0-50 ℃, preferably 0-30 ℃, more preferably 0-15 ℃, and the reaction residence time is 2-30min, preferably 2-10min, more preferably 4-8min.
6. The process according to claim 1, wherein the extract in step 1 is selected from one or more of acetone, toluene, xylene and methyl tert-butyl ether, preferably one or more of toluene, xylene, methyl tert-butyl ether.
7. The method according to claim 1, wherein the flow rate of the 3-oxo-cyclobutanecarbonyl chloride reaction solution in the step 1 is controlled to be 5-40mL/min, preferably 7-35mL/min, and the flow rate of the sodium azide reaction solution is controlled to be 5-40mL/min, preferably 7-35mL/min.
8. The process of claim 1, wherein the molar ratio of 3-oxocyclobutaneacyl azide intermediate to benzyl alcohol in step 2 is 1 (1-3).
9. The method according to claim 1, wherein the concentration of benzyl alcohol in step 2 is 0.1-5.0mol/L, and the flow rate in step 2 is controlled to be 1-10mL/min, preferably 3-6mL/min.
10. The process according to claim 1, characterized in that the reaction temperature in step 2 is 100-200 ℃, preferably 130-150 ℃, and the reaction residence time is 2-30min, preferably 2-10min, more preferably 5-10min.
11. The process according to claim 1, wherein the reaction back pressure in step 2 is 0.1-2MPa, preferably 0.1-1.1MPa.
12. The method of claim 1, wherein the microchannel reactor I in step 1 and the microchannel reactor II in step 2 are pipelined microreactors or chip microreactors.
13. The method according to claim 1, wherein the recrystallization solvent in step 3 is selected from ethanol/n-hexane, wherein the volume ratio of ethanol to n-hexane is 1: (1-10), preferably 1: (1-5).
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