CN111269282A - Method for preparing sofosbuvir intermediate by using continuous flow microchannel reactor - Google Patents
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Abstract
The invention relates to a process method for preparing (2'R) -N-benzoyl-2' -deoxy-2 '-fluoro-2' -methylcytidine-3 ',5' -dibenzoate, which belongs to the technical field of organic synthesis application, and is a new process method for preparing a target product within reaction time of dozens of seconds by using ((2R,3R,4R,5R) -3- (benzoyloxy) -5-chloro-4-fluoro-4-methyltetrahydrofuran-2-yl) methyl benzoate as a raw material and tin tetrachloride as a catalyst in a continuous flow microchannel reactor, wherein the material is introduced into the reactor through a counting pump, and then is heated, mixed and reacted to obtain a product; the method has the characteristics of simple and safe operation, high yield and short reaction time, and can realize continuous production; the product yield is more than 55 percent, and the purity reaches 99 percent.
Description
Technical Field
The invention relates to a continuous flow synthesis method for preparing (2'R) -N-benzoyl-2' -deoxy-2 '-fluoro-2' -methylcytidine-3 ',5' -dibenzoate by coupling ((2R,3R,4R,5R) -3- (benzoyloxy) -5-chloro-4-fluoro-4-methyltetrahydrofuran-2-yl) methyl benzoate, in particular to a continuous flow production process realized by a micro-channel continuous flow reactor, belonging to the field of chemical production processes.
Background
Viral hepatitis type c, hepatitis c for short, is a viral hepatitis caused by infection with Hepatitis C Virus (HCV). According to the statistics of the world health organization, the global infection rate is about 3%. The harm to the health and the life of patients is great, and the health and the life of the patients become serious social public health problems. In 2013, Sofosbuvir (trade name: Sovaldi, Chinese name Sofosbuvir) from Gilidide was approved by the FDA as a combined antiviral treatment regimen for the treatment of chronic hepatitis C infection. Approved by the European drug administration (EMEA) for marketing in countries of the European Union in 2014. The medicine has the advantages of high antiviral clearance rate, less adverse reaction and the like, becomes a heavy-pound medicine with global sales of over 100 hundred million dollars in 2014, and has wide market prospect.
(2'R) -N-benzoyl-2' -deoxy-2 '-fluoro-2' -methylcytidine-3 ',5' -dibenzoate (SFC) as a key intermediate of sofosbuvir, its structure is as follows:
at present, most of the synthesis methods still adopt the traditional mode. A specific conventional method is reported in patent CN101437524B as ((2R,3R,4R,5R) -3- (benzoyloxy)) -5-chloro-4-fluoro-4-methyltetrahydrofuran-2-yl) benzoic acid methyl ester (SFA) as starting material, and another intermediate N- (2- ((trimethylsilyl) oxy) pyrimidin-4-yl) benzamide (SFB) in chlorobenzene solvent; tin tetrachloride (SnCl) in Lewis acid catalyst4) In the presence of the catalyst, the catalyst is reacted for 10 to 30 hours at a temperature of between 60 and 90 ℃, and the yield is about 23 percent. In addition, the patents US2013/0324709A1, CN109422789A, CN109438537A, CN106810515A and the like all disclose the traditional synthesis method for synthesizing sofosbuvir, and the yield is 20-50%.
The traditional method has the defects that the reaction is not thorough, and the treatment after the reaction is not timely, so that the conversion of SFC to isomers (five-membered ring terminal position isomeric impurities) is caused, and the reaction selectivity is reduced; meanwhile, the SFA and the SFB are in contact reaction for a long time under the action of the catalyst, and impurities are obviously improved; due to low reaction contact efficiency, the consumption of the catalyst stannic chloride is large (generally 3-5 equivalent), which can cause excessive material waste and a large amount of solid waste; these are the key to the limitation of SFC yield in industrial production. In addition, the traditional synthesis method has the problems of high energy consumption, long reaction period, high cost and the like; and the continuous production can not be realized, the production capacity is limited, and the market competitiveness is reduced.
The micro-channel continuous flow reaction device is adopted for continuous production, the unique super-area contact and heart-shaped channel structure improves the mass transfer efficiency of materials, thereby improving the reaction yield, simultaneously controlling the temperature accurately, reducing the occurrence of side reactions, having almost no amplification effect from a laboratory to industrialization, simultaneously having the advantages of high product conversion rate, less heat dissipation, energy conservation, cost reduction and continuous production, and having no report of synthesizing SFC by a micro-channel continuous flow reaction method at present.
The invention content is as follows:
the invention provides a method for preparing a sofosbuvir intermediate by using a continuous flow microchannel reactor, namely a method for preparing SFA into SFC by using a corning microchannel reactor.
The invention specifically comprises the following contents:
a method for preparing a sofosbuvir intermediate by a continuous flow microchannel reaction comprises the following steps:
(1) adding N- (2- ((trimethylsilyl) oxy) pyrimidin-4-yl) benzamide into a chlorobenzene solution, and stirring to obtain a test solution with the number A;
(2) dissolving stannic chloride in chlorobenzene to obtain test solution B;
(3) dropwise adding the test solution B into the test solution A at 0-10 ℃, and mixing to obtain a test solution C;
(4) adding chlorobenzene into methyl ((2R,3R,4R,5R) -3- (benzoyloxy) -5-chloro-4-fluoro-4-methyltetrahydrofuran-2-yl) benzoate for dilution to obtain a test solution with a number D;
(5) heating the microchannel reactor to 70-85 ℃, and introducing the test solution numbered C and the test solution numbered D into the microchannel reactor simultaneously for reaction;
(6) introducing the solution after reaction into a dichloromethane solution for dilution, and then introducing into an acetic acid aqueous solution for quenching reaction;
(7) separating the system after the quenching reaction to obtain an organic phase, washing the organic phase by hydrochloric acid, distilling, cooling and adjusting the pH value;
(8) concentrating the organic phase after pH adjustment under reduced pressure to obtain a (2'R) -N-benzoyl-2' -deoxy-2 '-fluoro-2' -methylcytidine-3 ',5' -dibenzoate system containing chlorobenzene, cooling, crystallizing and centrifuging;
(9) and (2'R) -N-benzoyl-2' -deoxy-2 '-fluoro-2' -methylcytidine-3 ',5' -dibenzoate is obtained by thermally pulping the material obtained by centrifugation with a proper amount of methanol, cooling, crystallizing, centrifuging, collecting the solid and drying.
Further, the volume ratio of the N- (2- ((trimethylsilyl) oxy) pyrimidine-4-yl) benzamide to the chlorobenzene solution in the step (1) is 1: 9-11; the volume ratio of the tin tetrachloride to the chlorobenzene in the step (2) is 1: 1-1.5; in the step (4), the volume ratio of the methyl ((2R,3R,4R,5R) -3- (benzoyloxy) -5-chloro-4-fluoro-4-methyltetrahydrofuran-2-yl) benzoate to chlorobenzene is 1: 7-9.
Furthermore, the volume ratio of the test solution with the number B to the test solution with the number A in the step (3) is 1: 10-12.
Furthermore, in the step (5), the volume ratio of the test solution with the number C to the test solution with the number D is 1.1-1.8: 1. The feeding speed ratio of the test solution No. C and the test solution No. D is 1.1-1.8: 1.
Further, in the step (6), the mass ratio of the dichloromethane solution to the acetic acid aqueous solution is 8-9: 1; the mass ratio of acetic acid to water in the acetic acid aqueous solution is 1.5-2: 1; the mass ratio of the acetic acid aqueous solution in the step (6) to the methyl ((2R,3R,4R,5R) -3- (benzoyloxy) -5-chloro-4-fluoro-4-methyltetrahydrofuran-2-yl) benzoate in the step (4) is 1.5-1.8: 1.
further, the mass ratio of the tin tetrachloride in the step (2) to the methyl ((2R,3R,4R,5R) -3- (benzoyloxy) -5-chloro-4-fluoro-4-methyltetrahydrofuran-2-yl) benzoate in the step (4) is 1: 1.5-2.
Further, the reaction temperature of the microchannel reactor in the step (5) is 50-100 ℃; the feeding time of the test solution with the number C and the test solution with the number D is 10-15 min.
Further, the temperature of the dichloromethane solution in the step (6) is 30-35 ℃; the temperature of the acetic acid aqueous solution is 5-10 ℃.
Further, triethylamine is added in the step (7) to adjust the pH value, and the pH value is controlled to be 5-8.
Further, a reaction module is arranged in the microchannel reactor in the step (5), the reaction module is a two-feeding single-discharging module, and the reaction module is of a tubular structure, a T-shaped structure, a spherical structure with a baffle, a water-drop-shaped structure or a heart-shaped structure.
Controlling the reaction temperature by an external heat exchanger, and respectively setting the reaction temperature to be 50-100 ℃, preferably 70-85 ℃;
the number of tin tetrachloride equivalents is 1.5, 1.6, 1.7, 1.8, 1.9 and 2.0 times the number of SFA equivalents; tests prove that the optimal equivalent ratio is 1.6-1.8 equivalents.
The reaction time (residence time) is respectively set to 3 grades, the length is 120-160 seconds, the middle length is 60-100 seconds, the length is 10-50 seconds, and the reaction time is 30-90 seconds under better process conditions;
the reaction pressure ranges from 0.1 to 0.3Mpa, 0.3 to 0.8Mpa and 0.8 to 1.4Mpa, and the reaction pressure under the better process condition is 0.1 to 0.3 Mpa;
after the reaction is finished, quenching excessive stannic chloride by using acetic acid aqueous solution, standing and separating liquid, and carrying out acid washing, alkali dissociation, crystallization, pulping and purification on the obtained organic phase to obtain the product.
Compared with the prior art, the invention has the following beneficial effects because the technology is adopted:
1. the invention discloses a method for preparing a sofosbuvir intermediate by a continuous flow microchannel reaction, which greatly shortens the reaction time and only needs about 1 minute, while the traditional method needs hours and simultaneously reduces the formation of impurities;
2. the reaction has small heat release, low energy consumption and accurate reaction temperature control;
3. the feeding proportion of reaction materials is accurate, the reaction is fully mixed, and the yield is high;
4. the reaction is sufficiently quenched after treatment, the isomerization of the product is reduced, and the configuration proportion of the product is improved;
5. the micro-channel reactor is acid and alkali resistant, the module is convenient to assemble and disassemble, and can be adjusted according to the requirement;
6. can be continuously produced, and the system after the reaction can directly enter a post-treatment link.
Drawings
FIG. 1 is a schematic diagram of the structure of a reaction module in a microchannel reactor used in the present invention;
FIG. 2 is a block diagram of a microchannel reactor used in the present invention;
FIG. 3 is a process flow diagram of the preparation method of the present invention;
in the figure: 1. reaction module, 2, inlet valve, 3, outlet valve.
The specific implementation mode is as follows:
the present invention will be further illustrated with reference to the following specific embodiments.
A method for preparing a sofosbuvir intermediate by a continuous flow microchannel reaction is carried out according to the following steps with reference to a flow chart:
1) reacting N- (2- ((trimethylsilyl) oxy) pyrimidin-4-yl) benzamide (SFB) with N4Prepared by pre-preparing benzoyl cytosine and hexamethyldisilazane) into a chlorobenzene solution, cooling to 0-10 ℃ while stirring, and standing while keeping the temperature, wherein the test solution is numbered as A.
2) The stannic chloride was dissolved in chlorobenzene, and test solution B was designated.
3) And (4) dropwise adding the test solution B into the test solution A at 0-10 ℃, and mixing to obtain a test solution C.
4) (2R,3R,4R,5R) -3- (benzoyloxy) -5-chloro-4-fluoro-4-methyltetrahydrofuran-2-yl) benzoic acid methyl ester (SFA) was diluted with an appropriate amount of chlorobenzene to obtain test solution D.
5) And (3) putting dichloromethane at the outlet of the microchannel reactor, stirring, and controlling the temperature to be 30-35 ℃.
6) Preparing acetic acid, preparing an acetic acid aqueous solution from water, controlling the temperature to be 5-10 ℃, and placing the acetic acid aqueous solution at the downstream of dichloromethane at the outlet of the microchannel reactor.
7) Raising the temperature of the microchannel reactor to 70-85 ℃ in advance.
8) And (3) simultaneously pumping the C/D two test solutions into the microchannel reactor by using a feed pump, wherein the feed speed is set according to the volume ratio of the C/D two test solutions. After passing through the reactor, the mixture was diluted by flowing into a stirred dichloromethane solution and quenched by flowing into an aqueous acetic acid solution.
9) Separating the system after the quenching reaction, and washing the obtained organic phase twice by using 2N hydrochloric acid; and transferring the organic phase into a distillation reactor, cooling to 20-25 ℃, and dropwise adding triethylamine to adjust the pH value to 6-7.
10) Decompressing and concentrating the organic phase after pH adjustment to remove part of the low boiling point solvent; to obtain (2'R) -N-benzoyl-2' -deoxy-2 '-fluoro-2' -methylcytidine-3 ',5' -dibenzoate (SFC) system containing chlorobenzene; and cooling the system to 5 ℃, crystallizing for 3-4 hours, discharging and centrifuging. Thermally pulping the material obtained by centrifugation for 1h by using a proper amount of methanol, cooling to 20 ℃, centrifuging, and collecting solids; and drying to obtain the SFC with the yield of 60-72% and the purity of 97-99%.
The microchannel reactor used in the invention comprises an inlet valve 2, a reaction module 1 and an outlet valve 3 which are sequentially connected, wherein the reaction module 1 is a two-feeding single-discharging module, and the reaction module 1 has a tubular, T-shaped, spherical with a baffle, drop-shaped or heart-shaped structure.
Example 1:
a method for preparing a sofosbuvir intermediate by a continuous flow microchannel reaction is carried out according to the following steps:
1) adding 11g of SFB into 100ml of chlorobenzene, cooling to 5-10 ℃ under stirring, and standing while keeping the temperature, wherein the volume of the test solution A is about 110 ml.
2) 9.9g of tin tetrachloride (1.5 equivalents) was dissolved in 5.5ml of chlorobenzene, sample No. B, which was about 10 ml.
3) And (3) dropwise adding the test solution B into the test solution A at 5-10 ℃, and mixing to obtain about 120ml of test solution C.
4) 10g of SFA was diluted with 80ml of chlorobenzene to give about 90ml of test solution No. D.
5) And (3) placing 100ml of dichloromethane at the outlet of the microchannel reactor, stirring, and controlling the temperature to be 30-35 ℃.
6) Preparing 10g of acetic acid and 5g of aqueous solution, controlling the temperature to be 5-10 ℃, and placing the mixture at the downstream of dichloromethane at the outlet of the microchannel reactor.
7) Raising the temperature of the microchannel reactor to 70-85 ℃ in advance; reaction pressure: 0.3-0.8 Mpa; the residence time was 60 seconds;
8) and simultaneously pumping the C/D two test solutions into the microchannel reactor by using a feeding pump, wherein the feeding speeds are 12mL/min for the C solution and 9mL/min for the D solution respectively. C. And D, finishing the reaction of all the materials after the two test solutions react for 10min, wherein the reaction time of the test solutions in the microchannel reactor is about 60 s. After passing through the reactor, the mixture was diluted by flowing into a stirred dichloromethane solution (30 ℃ C.) and quenched by flowing into an aqueous acetic acid solution (10 ℃ C.).
9) Separating the system after the quenching reaction, and washing the obtained organic phase twice by using 2N hydrochloric acid; and transferring the organic phase into a distillation reactor, cooling to 20-25 ℃, and dropwise adding triethylamine to adjust the pH value to 6-7.
10) Decompressing and concentrating the organic phase after pH adjustment to remove part of the low boiling point solvent; obtaining an SFC system containing chlorobenzene; and cooling the system to 5 ℃, crystallizing for 3-4 hours, discharging and centrifuging. Thermally pulping the material obtained by centrifugation for 1h by using a proper amount of methanol, cooling to 20 ℃, centrifuging, and collecting solids; drying to obtain SFC with yield of 64% and purity of 99%.
Example 2:
12.6g of tin tetrachloride (1.9 equivalents) were added to example 1; other process conditions are unchanged;
and then the SFC is obtained by dilution, quenching, acid washing, alkaline hydrolysis, crystallization, pulping, centrifugation, drying and other operations, the yield is 60 percent, and the purity is 97.5 percent.
Example 3:
11.9g of tin tetrachloride (1.8 equivalents) were added as in example 1, the other process conditions being unchanged;
and then the SFC is obtained by dilution, quenching, acid washing, alkaline hydrolysis, crystallization, pulping, centrifugation, drying and other operations, the yield is 65 percent, and the purity is 98.5 percent.
Example 4:
according to the material proportion in the embodiment 1, raising the temperature of the microchannel reactor to 85-95 ℃ in advance; reaction pressure: 0.3-0.8 Mpa; the retention time is 60 seconds, and other process conditions are unchanged;
and then the SFC is obtained by dilution, quenching, acid washing, alkaline hydrolysis, crystallization, pulping, centrifugation, drying and other operations, the yield is 68 percent, and the purity is 97.2 percent.
Example 5:
according to the material proportion in the embodiment 1, raising the temperature of the microchannel reactor to 70-85 ℃ in advance; reaction pressure: 0.3-0.8 Mpa; the retention time is 120 seconds, and other process conditions are unchanged;
and then the SFC is obtained by dilution, quenching, acid washing, alkaline hydrolysis, crystallization, pulping, centrifugation, drying and other operations, the yield is 65 percent, and the purity is 98.2 percent.
Example 6:
according to the material proportion in the embodiment 1, raising the temperature of the microchannel reactor to 70-85 ℃ in advance; reaction pressure: 0.1-0.3 Mpa; the retention time is 60 seconds, and other process conditions are unchanged;
and then the SFC is obtained by dilution, quenching, acid washing, alkaline hydrolysis, crystallization, pulping, centrifugation, drying and other operations, the yield is 72 percent, and the purity is 98.9 percent.
The above-mentioned embodiments are merely preferred embodiments of the present invention, and should not be construed as limiting the present invention, and the scope of the present invention should be defined by the claims, and equivalents including technical features of the claims, i.e., equivalent modifications within the scope of the present invention.
Claims (10)
1. A method for preparing a sofosbuvir intermediate by a continuous flow microchannel reaction is characterized by comprising the following steps:
(1) adding N- (2- ((trimethylsilyl) oxy) pyrimidin-4-yl) benzamide into a chlorobenzene solution, and stirring to obtain a test solution with the number A;
(2) dissolving stannic chloride in chlorobenzene to obtain test solution B;
(3) dropwise adding the test solution B into the test solution A at 0-10 ℃, and mixing to obtain a test solution C;
(4) adding chlorobenzene into methyl ((2R,3R,4R,5R) -3- (benzoyloxy) -5-chloro-4-fluoro-4-methyltetrahydrofuran-2-yl) benzoate for dilution to obtain a test solution with a number D;
(5) heating the microchannel reactor to 70-85 ℃, and introducing the test solution numbered C and the test solution numbered D into the microchannel reactor simultaneously for reaction;
(6) introducing the solution after reaction into a dichloromethane solution for dilution, and then introducing into an acetic acid aqueous solution for quenching reaction;
(7) separating the system after the quenching reaction to obtain an organic phase, washing the organic phase by hydrochloric acid, distilling, cooling and adjusting the pH value;
(8) concentrating the organic phase after pH adjustment under reduced pressure to obtain a (2'R) -N-benzoyl-2' -deoxy-2 '-fluoro-2' -methylcytidine-3 ',5' -dibenzoate system containing chlorobenzene, cooling, crystallizing and centrifuging;
(9) and (2'R) -N-benzoyl-2' -deoxy-2 '-fluoro-2' -methylcytidine-3 ',5' -dibenzoate is obtained after the materials obtained by centrifugation are cooled, crystallized and centrifuged, and the solids are collected and dried.
2. The method for preparing the sofosbuvir intermediate by the continuous flow microchannel reaction according to claim 1, wherein: the volume ratio of the N- (2- ((trimethylsilyl) oxy) pyrimidine-4-yl) benzamide to the chlorobenzene solution in the step (1) is 1: 9-11; the volume ratio of the tin tetrachloride to the chlorobenzene in the step (2) is 1: 1-1.5; in the step (4), the volume ratio of the methyl ((2R,3R,4R,5R) -3- (benzoyloxy) -5-chloro-4-fluoro-4-methyltetrahydrofuran-2-yl) benzoate to chlorobenzene is 1: 7-9.
3. The method for preparing the sofosbuvir intermediate by the continuous flow microchannel reaction according to claim 1, wherein: and the volume ratio of the test solution with the number B to the test solution with the number A in the step (3) is 1: 10-12.
4. The method for preparing the sofosbuvir intermediate by the continuous flow microchannel reaction according to claim 1, wherein: in the step (5), the volume ratio of the test solution with the number C to the test solution with the number D is 1.1-1.8: 1;
the feeding speed ratio of the test solution No. C and the test solution No. D is 1.1-1.8: 1.
5. The method for preparing the sofosbuvir intermediate by the continuous flow microchannel reaction according to claim 1, wherein: the mass ratio of the dichloromethane solution to the acetic acid aqueous solution in the step (6) is 8-9: 1; the mass ratio of acetic acid to water in the acetic acid aqueous solution is 1.5-2: 1; the mass ratio of the acetic acid aqueous solution in the step (6) to the methyl ((2R,3R,4R,5R) -3- (benzoyloxy) -5-chloro-4-fluoro-4-methyltetrahydrofuran-2-yl) benzoate in the step (4) is 1.5-1.8: 1.
6. the method for preparing the sofosbuvir intermediate by the continuous flow microchannel reaction according to claim 1, wherein: the mass ratio of the tin tetrachloride in the step (2) to the methyl ((2R,3R,4R,5R) -3- (benzoyloxy) -5-chloro-4-fluoro-4-methyltetrahydrofuran-2-yl) benzoate in the step (4) is 1: 1.5-2.
7. The method for preparing the sofosbuvir intermediate by the continuous flow microchannel reaction according to claim 1, wherein: the reaction temperature of the microchannel reactor in the step (5) is 50-100 ℃; the feeding time of the test solution with the number C and the test solution with the number D is 10-15 min; the reaction time of the test solution in the microchannel reactor is 10-160 seconds.
8. The method for preparing the sofosbuvir intermediate by the continuous flow microchannel reaction according to claim 1, wherein: the temperature of the dichloromethane solution in the step (6) is 30-35 ℃; the temperature of the acetic acid aqueous solution is 5-10 ℃.
9. The method for preparing the sofosbuvir intermediate by the continuous flow microchannel reaction according to claim 1, wherein: and (4) adding triethylamine to adjust the pH value in the step (7), and controlling the pH value to be 5-8.
10. The process for preparing sofosbuvir intermediate in the continuous flow microchannel reactor of claim 1, wherein: and (5) arranging a reaction module in the microchannel reactor, wherein the reaction module is a two-feeding single-discharging module, and the reaction module is of a tubular structure, a T-shaped structure, a spherical structure with a baffle, a water-drop-shaped structure or a heart-shaped structure.
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| CN104379591A (en) * | 2012-05-29 | 2015-02-25 | 弗·哈夫曼-拉罗切有限公司 | Process for the preparation of 2-deoxy-2-fluoro-2-methyl-d-ribofuranosyl nucleoside compounds |
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| CN104379591A (en) * | 2012-05-29 | 2015-02-25 | 弗·哈夫曼-拉罗切有限公司 | Process for the preparation of 2-deoxy-2-fluoro-2-methyl-d-ribofuranosyl nucleoside compounds |
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| Title |
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| 彭金辉: "《微流体溶剂萃取技术》", 30 June 2015 * |
| 杨光富: "《有机合成》", 31 August 2016 * |
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Application publication date: 20200612 |