CN113896658A - Method for synthesizing darunavir intermediate by using microchannel reactor - Google Patents
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- 238000000034 method Methods 0.000 title claims abstract description 30
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- NUMJNKDUHFCFJO-VQTJNVASSA-N 4-amino-n-[(2r,3s)-3-amino-2-hydroxy-4-phenylbutyl]-n-(2-methylpropyl)benzenesulfonamide Chemical compound C([C@H](N)[C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)C1=CC=CC=C1 NUMJNKDUHFCFJO-VQTJNVASSA-N 0.000 claims abstract description 17
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- YMARZQAQMVYCKC-OEMFJLHTSA-N amprenavir Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1COCC1)C1=CC=CC=C1 YMARZQAQMVYCKC-OEMFJLHTSA-N 0.000 description 1
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- 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
- C07C269/06—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 by reactions not involving the formation of carbamate groups
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/0093—Microreactors, e.g. miniaturised or microfabricated reactors
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
- B01J23/38—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals
- B01J23/40—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals of the platinum group metals
- B01J23/44—Palladium
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/38—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reaction of ammonia or amines with sulfonic acids, or with esters, anhydrides, or halides thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
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Abstract
The invention discloses a method for synthesizing a darunavir intermediate by using a microchannel reactor. The synthesis method comprises the following steps: 1-benzyl-2, 3-epoxy N-propyl-tert-butyl carbamate is used as a starting material, and the darunavir intermediate 4-amino-N- (2R, 3S) - (3-amino-2-hydroxy-4-phenyl-butyl) -N-isobutyl-benzenesulfonamide is generated through amination, sulfonylation, Boc protecting group removal and microchannel hydrogenation reduction reaction. The method has the advantages of simple operation, safety, environmental protection, easy batch synthesis, low energy consumption and high purity.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a method for synthesizing a darunavir intermediate by using a microchannel reactor, which is suitable for synthesizing a darunavir intermediate 4-amino-N- (2R, 3S) - (3-amino-2-hydroxy-4-phenyl-butyl) -N-isobutyl-benzenesulfonamide for treating AIDS.
Background
Darunavir (Darunavir) is a drug developed by hadean pharmaceutical corporation for the treatment of aids, and Darunavir Ethanolate (Darunavir ethanol) was first marketed in 2006 in the united states and canada.
Darunavir, a novel non-peptide antiretroviral protease inhibitor for aids therapy, was first developed successfully by Tibotec, robiong pharmaceutical iceland, is currently the most bioavailable of the 6 protease inhibitors (saquinavir, ritonavir, indinavir, nelfinavir, amprenavir and ABT378/r) and works by blocking the formation process of the release of new, mature virions from the infected host cell surface, inhibiting viral proteases. When the product is used for a long time, the product can generally reduce HIV viral vectors in blood, increase the count of CD4 cells, reduce the chance of infecting AIDS, improve the quality of life and prolong life. Suitable for adults infected with AIDS virus who have not been able to take the existing antiretroviral drugs, and the drugs must be used in combination with ritonavir or other antiretroviral agents with low dosage to improve the drug effect. The antiviral activity in vitro can be evaluated by combating acute and chronic infected lymphoblasts and lymphocytes in the blood of the peripheral system, with an IC50 of 0.012-0.08 mmol/L for acute infected cells and 0.41mmol/L for chronic infected cells. The dose of oral administration is recommended to be 1 time 1200mg and 1 day 2 times, and the dose should be decreased for patients with mild to moderate liver dysfunction and renal dysfunction. Adverse reactions of darunavir mainly include gastrointestinal reactions, flushing, itching, perioral numbness, depression, mood disorders, taste disorders and the like. The product is not recommended for patients with moderate to severe liver dysfunction. Because the component contains the sulfonamide group, the component is forbidden to be used by patients allergic to sulfanilamide and patients allergic to any component in the prescription of the product.
Darunavir Ethanolate (Darunavir ethanol) was first marketed in 2006 in the united states and canada under the trade name prezita, and subsequently in several countries, australia, japan, etc. The darunavir ethanolate and Cobicistat compound PREZCOBIX was also marketed in 2014.
The structural formula of darunavir is as follows:
the darunavir intermediate 4-amino-N- (2R, 3S) - (3-amino-2-hydroxy-4-phenyl-butyl) -N-isobutyl-benzenesulfonamide is an N-1 step intermediate for synthesizing darunavir, and the darunavir can be obtained by further reaction. In the synthesis process, p-nitrobenzenesulfonyl chloride is used as a raw material, and reduction is required to be carried out on nitro after the reaction is finished.
Microreactors, i.e. microchannel reactors, are microreactors with channel equivalent diameters of between 10 and 300 microns (or 1000 microns) fabricated using precision machining techniques, the "micro" of which means that the channels for the process fluids are on the order of microns and not the small physical dimensions of the microreactor equipment or the small product yields. The microreactors can contain millions of microchannels and thus achieve high throughput. The biggest defect of the micro-structure of the micro-reactor is that solid materials can not pass through the micro-channel, and if a large amount of solids are generated in the reaction, the micro-channel is easy to block, so that the production can not be continuously carried out. The micro-reactor has been widely researched by the academic communities at home and abroad so far, the principle and the characteristics of the micro-reactor are well known, and the micro-reactor has favorable performances in the aspects of design, manufacture, integration, amplification and the like. However, the research on the method is not mature enough, the traditional theory of 'three passes and one reverse' must be modified, supplemented and innovated, some principles of the reaction are not discussed clearly, and a great deal of work is needed. In addition, there are many technical difficulties in its manufacture, in the wall-loading of the catalyst and in the automatic control of the system, and it is necessary to carry out a deep study of surface and interface phenomena, transfer laws, reaction characteristics and amplification integration in the micro-reaction system.
In the 21 st century, due to a series of problems such as environmental deterioration and energy depletion, the chemical industry faces unprecedented opportunities and challenges, and due to the advantages of the microreactor, the scientific community is dedicated to exploring a new reaction path to make the chemical production more economical and environment-friendly. It is therefore necessary to believe that microreactors will play a great role in the chemical industry.
The synthesis methods of darunavir intermediates reported in the prior literature mainly comprise the following steps:
the method comprises the following steps: the following synthetic routes are reported in Bioorganic & Medicinal Chemistry Letters 8(1998) 687-:
the reaction route uses azide with high risk, hydrogenation reduction is high in pressure and exothermic, operation is dangerous, and large-scale industrial production is difficult.
The method 2 comprises the following steps: the synthetic route reported in patent US6248775 is as follows:
when the route is used for reducing the nitro and debenzyloxy carbonyl protecting group, a large amount of heat is released, a plurality of side reactions are generated, and the reaction selectivity is reduced.
The method 3 comprises the following steps: the reported synthetic routes of patents US20120251826a1 and US7772411B2 starting from 1-benzyl-2, 3-epoxy-n-propyl-tert-butyl carbamate are as follows:
the route adopts palladium carbon as a catalyst, reduces nitro groups by hydrogenation, releases heat under high pressure, and has certain potential safety hazard.
The method 4 comprises the following steps: the synthetic route reported in patent US20150141382a1 is as follows:
the route adopts Raney nickel to catalyze hydrogen for reduction, the Raney nickel is easy to spontaneously combust, the reaction time is long, more impurities are easy to generate, the heat is released at high pressure in the production process, and the potential safety hazard is large.
Disclosure of Invention
Therefore, in order to overcome the problems of complex process, more solvent requirement, easy generation of danger caused by violent explosion, potential safety hazard in large-scale production and the like of the conventional reduction preparation method of the darunavir intermediate, the invention provides a method for synthesizing the darunavir intermediate by using a microchannel reactor, in particular to a microchannel hydrogenation reduction preparation method of the darunavir intermediate 4-amino-N- (2R, 3S) - (3-amino-2-hydroxy-4-phenyl-butyl) -N-isobutyl-benzenesulfonamide, which uses 1-benzyl-2, 3 epoxy N-propyl-tert-butyl carbamate as a starting material to generate the darunavir intermediate 4-amino-N- (2R through amination, sulfonylation, Boc protecting group removal and microchannel hydrogenation reduction reactions, 3S) - (3-amino-2-hydroxy-4-phenyl-butyl) -N-isobutyl-benzenesulfonamide.
The technical scheme adopted by the invention for solving the technical problems is as follows: a method for synthesizing a darunavir intermediate by using a microchannel reactor comprises the following steps:
s1, see patent US20150141382a1, to synthesize 4-nitro-N- (2R, 3S) - (3-amino-2-hydroxy-4-phenyl-butyl) -N-isobutyl-benzenesulfonamide hydrochloride starting from 1-benzyl-2, 3-epoxy-N-propyl-tert-butyl carbamate;
s2, synthesizing a darunavir intermediate through hydrogenation reduction reaction;
the S2 specifically includes the following steps:
(1) adding 4-nitro-N- (2R, 3S) - (3-amino-2-hydroxy-4-phenyl-butyl) -N-isobutyl-benzenesulfonamide hydrochloride into an organic solvent A for dissolving, adding a hydrogenation reduction catalyst, and stirring to obtain a mixture serving as a material a;
(2) introducing the material a and hydrogen into a microchannel reactor for reaction, and filtering the reaction solution after the reaction is finished to obtain a filtrate;
(3) and concentrating, neutralizing, cooling and crystallizing the obtained filtrate to obtain the darunavir intermediate 4-amino-N- (2R, 3S) - (3-amino-2-hydroxy-4-phenyl-butyl) -N-isobutyl-benzenesulfonamide.
Further, in the step (1) of S2, the organic solvent a is one of methanol, ethanol, isopropanol, and tetrahydrofuran.
Further, in the step (1) of S2, the mass ratio of 4-nitro-N- (2R, 3S) - (3-amino-2-hydroxy-4-phenyl-butyl) -N-isobutyl-benzenesulfonamide hydrochloride to the solvent a is (0.05-0.3): 1.
further, the reaction temperature in the microchannel reactor in the step (2) of S2 is 50-100 ℃.
Further, in the step (2) of S2, the molar ratio of the hydrogen to the 4-nitro-N- (2R, 3S) - (3-amino-2-hydroxy-4-phenyl-butyl) -N-isobutyl-benzenesulfonamide hydrochloride in the material a is (2.2-2.5): 1.
Further, the cooling temperature for cooling and crystallizing in the step (3) of S2 is 0-10 ℃.
Further, the reaction pressure in the microchannel reactor in the step (2) of S2 is 6-10 MPa.
Further, in the step (1) of S2, the hydrogenation reduction catalyst is palladium carbon, and palladium accounts for 5% of the total mass of the catalyst.
The invention has the beneficial effects that: the invention has reasonable design, simple and easy operation of the synthesis method and the following advantages:
(1) the invention provides a green hydrogenation reduction technology for safely synthesizing a darunavir intermediate 4-amino-N (2R, 3S) - (3-amino-2-hydroxy-4-phenyl-butyl) -N-isobutyl-benzenesulfonamide;
(2) due to the unique micro-structural design of the microchannel reactor, the material liquid of the reaction can realize continuous on-line mixing, preheating and reaction, even if two phases or three phases are not dissolved, the mixing reaction can be completed in a short time, the mixing efficiency of the microchannel reactor is improved by more than 100 times compared with that of the traditional stirring hydrogenation reaction kettle, the whole reaction time can be shortened to about 50 seconds from twenty hours to several hours, the impurity content of the product is greatly reduced due to overlarge local concentration in the synthesis process, and the purity and the yield of the product are improved;
(3) the method takes hydrogen as a reducing agent in the hydrogenation reduction process, reduces the consumption of the hydrogen under the catalysis of carbon-loaded noble metal palladium and under the condition of solid-liquid-gas mixing, overcomes the defects of unsafe operation, insufficient reaction and the like in the kettle type reaction process, ensures the safety of the preparation process, and has the advantages of simple operation, safety, environmental protection, high purity, low energy consumption, high purity and easy batch synthesis.
Drawings
The invention is further illustrated with reference to the following figures and examples.
FIG. 1 is a block diagram of a microchannel continuous flow reactor of the present invention.
Detailed Description
The invention will now be further described with reference to the accompanying drawings and examples.
The structure of the micro-channel continuous flow reactor used in the following embodiment is shown in fig. 1, and comprises a preheating module 1, a preheating module 2, a reaction module group and a cooling quenching module, wherein the preheating module 1 and the preheating module 2 are arranged in parallel, the preheating module 1 and the preheating module 2 are both connected in series with the reaction module group, and the other end of the reaction module group is connected in series with the cooling quenching module.
A method for synthesizing a darunavir intermediate by using a microchannel reactor comprises the following steps:
s1, see patent US20150141382a1, to synthesize 4-nitro-N- (2R, 3S) - (3-amino-2-hydroxy-4-phenyl-butyl) -N-isobutyl-benzenesulfonamide hydrochloride starting from 1-benzyl-2, 3-epoxy-N-propyl-tert-butyl carbamate;
s2, synthesizing a darunavir intermediate through hydrogenation reduction reaction;
the step S2 specifically includes the following steps:
(1) adding 4-nitro-N- (2R, 3S) - (3-amino-2-hydroxy-4-phenyl-butyl) -N-isobutyl-benzenesulfonamide hydrochloride into an organic solvent A for dissolving, adding a hydrogenation reduction catalyst, and stirring to obtain a mixture serving as a material a;
(2) introducing the material a and hydrogen into a microchannel reactor for reaction, and filtering the reaction solution after the reaction is finished to obtain a filtrate;
(3) and concentrating, neutralizing, cooling and crystallizing the obtained filtrate to obtain the darunavir intermediate 4-amino-N- (2R, 3S) - (3-amino-2-hydroxy-4-phenyl-butyl) -N-isobutyl-benzenesulfonamide.
The synthetic route of S1 is as follows:
the synthetic route of S2 is as follows:
example 1
A method for synthesizing a darunavir intermediate by using a microchannel reactor comprises the following steps:
(1) weighing 50.0g (108mmol) of 4-nitro-N- (2R, 3S) - (3-amino-2-hydroxy-4-phenyl-butyl) -N-isobutyl-benzenesulfonyl amine hydrochloride, dissolving in 350.0g of methanol serving as a solvent A, and stirring to dissolve the solution;
(2) weighing 5.0g of palladium-carbon (palladium accounts for 5 percent of the total mass of the catalyst), adding the palladium-carbon into the slurry, and fully stirring to obtain a mixture which is a material a;
(3) conveying the material a to a preheating module 1 by a material pump A at a speed of 30ml/min for preheating;
(4) controlling the hydrogen to be conveyed to the preheating module 2 by a flow meter B at a speed of 400ml/min for activation;
(5) introducing the material a treated in the step (3) and the step (4) and hydrogen into a reaction module group for reaction, wherein the molar ratio of the hydrogen to the 4-nitro-N- (2R, 3S) - (3-amino-2-hydroxy-4-phenyl-butyl) -N-isobutyl-benzenesulfonamide hydrochloride in the material a is 2.4: 1; the reaction temperature is 90 ℃, the reaction pressure is 10MPa, the residence time is 49s, and the temperature of the cooling quenching module is 25 ℃;
(6) collecting reaction liquid after the reaction is finished, and filtering to obtain filtrate, wherein the HPLC purity of materials in the filtrate is 99.53%; adding 10 wt% of sodium hydroxide aqueous solution into the filtrate, adjusting the pH value to 7-8, concentrating under reduced pressure until a large amount of solid is separated out, adding 350g of water, cooling to 0 ℃, stirring for 1h at the temperature of below 5 ℃, filtering, leaching the filter cake with 50 wt% of methanol aqueous solution, and drying to obtain 40.3g of 4-amino-N- (2R, 3S) - (3-amino-2-hydroxy-4-phenyl-butyl) -N-isobutyl-benzenesulfonamide with the HPLC purity of 99.6% and the mass yield of 95%.
Example 2
This example is different from example 1 in that: in this example, the amount of palladium-carbon used in step (2) was 1.5g, the HPLC purity of the material in the filtrate obtained by filtration was 97.26%, and 36.9g of 4-amino-N- (2R, 3S) - (3-amino-2-hydroxy-4-phenyl-butyl) -N-isobutyl-benzenesulfonamide were obtained, which had an HPLC purity of 99.0% and a mass yield of 87%.
Example 3
This example is different from example 1 in that: in this example, solvent A in step (1) was ethanol, and the HPLC purity of the material in the filtrate obtained by filtration was 99.49%, and thus 39.9g of 4-amino-N- (2R, 3S) - (3-amino-2-hydroxy-4-phenyl-butyl) -N-isobutyl-benzenesulfonamide was obtained, which had an HPLC purity of 99.6% and a mass yield of 94%.
Example 4
This example is different from example 1 in that: in this example, the solvent A in step (1) was isopropanol, and the HPLC purity of the material in the filtrate obtained by filtration was 99.45%, and 39.5g of 4-amino-N- (2R, 3S) - (3-amino-2-hydroxy-4-phenyl-butyl) -N-isobutyl-benzenesulfonamide was obtained, with an HPLC purity of 99.6% and a mass yield of 93%.
Example 5
This example is different from example 1 in that: in this example, solvent A in step (1) was tetrahydrofuran, and the HPLC purity of the material in the filtrate obtained by filtration was 99.25%, and thus 39.1g of 4-amino-N- (2R, 3S) - (3-amino-2-hydroxy-4-phenyl-butyl) -N-isobutyl-benzenesulfonamide was obtained, with an HPLC purity of 99.6% and a mass yield of 92%.
Example 6
This example is different from example 1 in that: in this example, the reaction temperature in step (5) was 80 ℃, the HPLC purity of the material in the filtrate obtained by filtration was 98.83%, and 37.8g of 4-amino-N- (2R, 3S) - (3-amino-2-hydroxy-4-phenyl-butyl) -N-isobutyl-benzenesulfonamide was obtained, which had an HPLC purity of 99.2% and a mass yield of 89%.
Example 7
This example is different from example 1 in that: in this example, the reaction temperature in step (5) was 60 ℃, the HPLC purity of the material in the filtrate obtained by filtration was 96.43%, and 36.1g of 4-amino-N- (2R, 3S) - (3-amino-2-hydroxy-4-phenyl-butyl) -N-isobutyl-benzenesulfonamide was obtained, which had an HPLC purity of 98.3% and a mass yield of 85%.
Example 8
This example is different from example 2 in that: in this example, the reaction temperature in step 5 was 100 ℃, the HPLC purity of the material in the filtrate obtained by filtration was 99.23%, and 40.1g of 4-amino-N- (2R, 3S) - (3-amino-2-hydroxy-4-phenyl-butyl) -N-isobutyl-benzenesulfonamide was obtained, which had an HPLC purity of 99.6% and a mass yield of 95%.
Comparative example 1
A method for producing 4-amino-N- (2R, 3S) - (3-amino-2-hydroxy-4-phenyl-butyl) -N-isobutyl-benzenesulfonamide in an autoclave type specifically comprises the following steps:
adding 350g of methanol into a 2L high-pressure reaction kettle, stirring and adding 50g of 4-nitro-N- (2R, 3S) - (3-amino-2-hydroxy-4-phenyl-butyl) -N-isobutyl-benzenesulfonamide hydrochloride, adding 5g of palladium carbon (palladium accounts for 5% of the total mass of the catalyst), introducing hydrogen after nitrogen replaces air for multiple times, reacting at the temperature of 45-50 ℃ and the pressure of 0.4Mpa for 25 hours, replacing hydrogen with nitrogen after the reaction is finished, filtering, washing palladium carbon with a small amount of methanol, adjusting the pH value to 7-8 by 10% of sodium hydroxide aqueous solution, concentrating under reduced pressure to separate out a large amount of solids, adding 350g of water, cooling to the temperature of below 10 ℃, stirring for 1 hour, performing suction filtration and drying to obtain 4-amino-N- (2R, 3S) - (3-amino-2-hydroxy-4-phenyl-butyl) -N-isobutyl-benzenesulfonamide hydrochloride 36.6g of isobutyl-benzenesulfonamide, 98.0% purity by HPLC and 86% mass yield.
By comparing inventive examples 1-8 with comparative example 1: in traditional high-pressure hydrogenation, need replace the air with nitrogen before the reaction, need nitrogen replacement hydrogen many times after the reaction, complex operation, hydrogen use amount is too big, and hydrogenation cauldron reaction time is long easily produces more accessory substances, influences product purity to high-pressure is exothermic has potential safety hazard. The invention utilizes the microchannel reactor for reaction, greatly shortens the reaction residence time of the materials in the reactor (from 20 hours of the traditional kettle type reaction to 60 seconds less than the reaction residence time), and has difficult generation of byproducts and high product purity.
In light of the foregoing description of the preferred embodiment of the present invention, many modifications and variations will be apparent to those skilled in the art without departing from the spirit and scope of the invention. The technical scope of the present invention is not limited to the content of the specification, and must be determined according to the scope of the claims.
Claims (8)
1. A method for synthesizing a darunavir intermediate by using a microchannel reactor is characterized by comprising the following steps: the method specifically comprises the following steps:
s1, synthesizing 4-nitro-N- (2R, 3S) - (3-amino-2-hydroxy-4-phenyl-butyl) -N-isobutyl-benzenesulfonamide hydrochloride by using 1-benzyl-2, 3-epoxy N-propyl-tert-butyl carbamate as a starting material;
s2, synthesizing a darunavir intermediate through hydrogenation reduction reaction;
the S2 specifically includes the following steps:
(1) adding 4-nitro-N- (2R, 3S) - (3-amino-2-hydroxy-4-phenyl-butyl) -N-isobutyl-benzenesulfonamide hydrochloride into an organic solvent A for dissolving, adding a hydrogenation reduction catalyst, and stirring to obtain a mixture serving as a material a;
(2) introducing the material a and hydrogen into a microchannel reactor for reaction, and filtering the reaction solution after the reaction is finished to obtain a filtrate;
(3) and concentrating, neutralizing, cooling and crystallizing the obtained filtrate to obtain the darunavir intermediate 4-amino-N- (2R, 3S) - (3-amino-2-hydroxy-4-phenyl-butyl) -N-isobutyl-benzenesulfonamide.
2. The method for synthesizing the darunavir intermediate by using the microchannel reactor as claimed in claim 1, wherein: and (2) in the step (1) of S2, the organic solvent A is one of methanol, ethanol, isopropanol and tetrahydrofuran.
3. The method for synthesizing the darunavir intermediate by using the microchannel reactor as claimed in claim 1, wherein: the mass ratio of the 4-nitro-N- (2R, 3S) - (3-amino-2-hydroxy-4-phenyl-butyl) -N-isobutyl-benzenesulfonamide hydrochloride to the solvent A in the step (1) of S2 is (0.05-0.3): 1.
4. the method for synthesizing the darunavir intermediate by using the microchannel reactor as claimed in claim 1, wherein: and (3) in the step (2) of S2, the reaction temperature in the microchannel reactor is 50-100 ℃.
5. The method for synthesizing the darunavir intermediate by using the microchannel reactor as claimed in claim 1, wherein: the molar ratio of the hydrogen in the step (2) of S2 to the 4-nitro-N- (2R, 3S) - (3-amino-2-hydroxy-4-phenyl-butyl) -N-isobutyl-benzenesulfonamide hydrochloride in the material a is (2.2-2.5): 1.
6. The method for synthesizing the darunavir intermediate by using the microchannel reactor as claimed in claim 1, wherein: and (3) cooling and crystallizing at the cooling temperature of 0-10 ℃ in the step (3) of S2.
7. The method for synthesizing the darunavir intermediate by using the microchannel reactor as claimed in claim 1, wherein: and (3) in the step (2) of S2, the reaction pressure in the microchannel reactor is 6-10 MPa.
8. The method for synthesizing the darunavir intermediate by using the microchannel reactor as claimed in claim 1, wherein: the hydrogenation reduction catalyst in the step (1) of S2 is palladium-carbon, and palladium accounts for 5% of the total mass of the catalyst.
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