CN113880838A - Method for synthesizing valganciclovir hydrochloride by using microchannel reactor - Google Patents
Method for synthesizing valganciclovir hydrochloride by using microchannel reactor Download PDFInfo
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- CN113880838A CN113880838A CN202111347104.6A CN202111347104A CN113880838A CN 113880838 A CN113880838 A CN 113880838A CN 202111347104 A CN202111347104 A CN 202111347104A CN 113880838 A CN113880838 A CN 113880838A
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- ZORWARFPXPVJLW-MTFPJWTKSA-N [2-[(2-amino-6-oxo-3h-purin-9-yl)methoxy]-3-hydroxypropyl] (2s)-2-amino-3-methylbutanoate;hydron;chloride Chemical compound Cl.N1C(N)=NC(=O)C2=C1N(COC(CO)COC(=O)[C@@H](N)C(C)C)C=N2 ZORWARFPXPVJLW-MTFPJWTKSA-N 0.000 title claims abstract description 42
- 229960004983 valganciclovir hydrochloride Drugs 0.000 title claims abstract description 42
- 238000000034 method Methods 0.000 title claims abstract description 21
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 17
- 239000000463 material Substances 0.000 claims abstract description 58
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 28
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 14
- 239000001257 hydrogen Substances 0.000 claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims description 66
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 56
- 238000003756 stirring Methods 0.000 claims description 35
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
- 238000001914 filtration Methods 0.000 claims description 24
- 238000005406 washing Methods 0.000 claims description 20
- 238000001816 cooling Methods 0.000 claims description 19
- 238000002156 mixing Methods 0.000 claims description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 239000008213 purified water Substances 0.000 claims description 17
- 239000012043 crude product Substances 0.000 claims description 16
- 239000000047 product Substances 0.000 claims description 16
- 239000002002 slurry Substances 0.000 claims description 16
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 14
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 14
- 239000012065 filter cake Substances 0.000 claims description 13
- 238000001291 vacuum drying Methods 0.000 claims description 11
- 239000003054 catalyst Substances 0.000 claims description 9
- 239000012295 chemical reaction liquid Substances 0.000 claims description 9
- 238000005303 weighing Methods 0.000 claims description 9
- 239000000706 filtrate Substances 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 6
- 238000004321 preservation Methods 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 5
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- 238000004821 distillation Methods 0.000 claims description 4
- -1 (2S) -2- ((2-amino-6-oxo-1H-purine-9 (6H) -yl) methoxy) -3-hydroxypropyl Chemical group 0.000 claims description 2
- 238000012805 post-processing Methods 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 239000011541 reaction mixture Substances 0.000 claims description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 8
- 238000005984 hydrogenation reaction Methods 0.000 abstract description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 238000004519 manufacturing process Methods 0.000 description 6
- 238000004140 cleaning Methods 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 239000007789 gas Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 229960002963 ganciclovir Drugs 0.000 description 3
- IRSCQMHQWWYFCW-UHFFFAOYSA-N ganciclovir Chemical compound O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 206010011831 Cytomegalovirus infection Diseases 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 206010038910 Retinitis Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000002485 combustion reaction Methods 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 231100000024 genotoxic Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- GSYSFVSGPABNNL-UHFFFAOYSA-N methyl 2-dimethoxyphosphoryl-2-(phenylmethoxycarbonylamino)acetate Chemical group COC(=O)C(P(=O)(OC)OC)NC(=O)OCC1=CC=CC=C1 GSYSFVSGPABNNL-UHFFFAOYSA-N 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
-
- 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
- Y02P20/584—Recycling of catalysts
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for synthesizing valganciclovir hydrochloride by a microchannel reactor, which comprises the steps of respectively preparing a material A and a material B, adding the materials A and B into the microchannel reactor, and then introducing hydrogen to carry out hydrogenation reaction to obtain valganciclovir hydrochloride; meanwhile, the palladium residue in large-scale production can be reduced, and the product yield and purity can be improved.
Description
Technical Field
The invention relates to a method for synthesizing valganciclovir hydrochloride by a microchannel reactor, belonging to the technical field of medicines.
Background
Valganciclovir hydrochloride is an oral cell-resistant (CMV) infection drug developed by roche switzerland and approved by FDA in us5 months in 2001 for marketing. Clinically used for treating acute retinitis of patients with acquired immunodeficiency syndrome caused by CMV infection; preventing and treating CMV infection in organ transplant patients. The product is a prodrug of ganciclovir, is rapidly hydrolyzed into ganciclovir by esterase in intestinal tract and liver cells after being taken orally, thereby exerting the drug effect, has the oral absorption bioavailability 10 times that of ganciclovir, greatly reduces the toxicity, and has wide market prospect. In China, valganciclovir hydrochloride belongs to a clinically urgent medicine, but no domestic variety is on the market, the valganciclovir hydrochloride completely depends on import, the price is high, and the economic burden of patients is heavy.
Valganciclovir hydrochloride has a complex structure and high synthesis difficulty, and the synthesis of valganciclovir hydrochloride is researched by patents US5840891, WO9727194, US5700936, CN107163050 and the like, and different routes are optimized at different angles, but all reported routes relate to a key step, and a benzyloxycarbonyl protecting group needs to be removed, and the chemical reaction formula is as follows:
currently, there are two main methods for deprotection of N-benzyloxycarbonyl (Cbz): 1) acid hydrolysis and cracking: when a hydrobromic acid/acetic acid system is generally used, when a Cbz protecting group is removed, the product is difficult to avoid with color, and benzyl bromide which is a potential genotoxic impurity generated by decomposition generates some side reactions and is difficult to remove. 2) And (3) catalytic hydrogenolysis: the method is characterized in that cheap and environment-friendly hydrogen is used as a reducing agent, and palladium-carbon, Raney nickel and other heavy metal catalysts are reduced to obtain a target product, and the target product is a main method for synthesizing valganciclovir hydrochloride at present, but the reaction is usually carried out under high pressure, and the flammable and explosive properties of the hydrogen cause great potential safety hazard and great operation difficulty in the large-scale production process; moreover, the reaction can be completed under the catalysis of noble metals such as Pd, Ni and the like, and the catalyst can not be dissolved in a reaction system generally, so that the catalytic hydrogenation reaction belongs to a typical gas-liquid-solid three-phase mixed reaction, the mixing efficiency is low, the reaction must be carried out at high temperature and high pressure for a long time, otherwise, the complete reaction of raw materials is difficult to ensure, and the conventional hydrogenation kettle after amplification has poor mixing effect, so that the reaction time is greatly increased, and the product has poor purity and low yield.
In summary, the main methods for synthesizing valganciclovir hydrochloride at present have the problems of serious environmental pollution, poor safety, high operation difficulty, low product yield, poor purity and the like.
In order to solve the above problems, it is considered to use a microchannel reactor because the microchannel reactor can shorten the reaction time of a general chemical reaction and also solve the problem of releasing a large amount of heat and a large amount of by-products in the reaction.
Adding the intermediate into methanol in a laboratory, adding hydrochloric acid and 10% palladium-carbon under stirring, fully stirring to form a material A, conveying the material A into a first module of a microchannel reactor through a slurry pump, preheating and mixing, then feeding into a reaction module group of the microchannel reactor, conveying hydrogen to the reaction module group of the microchannel reactor to react with the preheated material in the reaction module group, wherein the reaction temperature is 100 ℃, the residence time of the reaction is 28s, and the reaction pressure is 0.6MPa, collecting reaction liquid flowing out from an outlet of a cooling module (the temperature of the cooling module is 10 ℃), performing post-treatment, wherein the post-treatment refers to filtering and recovering a catalyst, decompressing and distilling and recovering a solvent, adding purified water and isopropanol into residues, and performing vacuum drying at 50 ℃ for 12 hours to obtain a valganciclovir hydrochloride crude product, wherein the yield is greater than 85.0%, the purity is greater than 98.5%, and the palladium residue is less than 15 ppm.
And adding purified water and activated carbon into the crude product obtained in the previous step, stirring for 0.5h, filtering, adding isopropanol into the filtrate, keeping the temperature at 0-10 ℃, stirring for 2h, filtering, washing the filter cake with isopropanol, and vacuum-drying at 50 ℃ for 12h to obtain a valganciclovir hydrochloride pure product, wherein the yield is more than 85.0%, the purity is more than 99.0%, and the palladium residue is less than 3 ppm.
The laboratory effect is good, the large-scale production is carried out, however, after the large-scale production is carried out, the blockage problem is serious, the production efficiency is influenced, and the palladium residue is also greatly increased after the detection, the palladium residue of a crude product is 587ppm, and the palladium residue of a pure product is 178 ppm. The addition amount of the laboratory intermediate is 100g, the time of material flow is only 10-20min, the addition amount of the intermediate in the large-scale production is 50kg, the time of material flow is 80-170h, the reaction needs to be cleaned every 2 hours, the materials need to be discharged completely during cleaning, then strong acid is introduced for cleaning, 5-6 hours are needed for cleaning once, and the production efficiency is seriously influenced.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a method for synthesizing valganciclovir hydrochloride by using a microchannel reactor, which can greatly improve the blockage problem of the microchannel reactor in large-scale production; meanwhile, the palladium residue in the molding production can be reduced, and the product yield and purity can be improved.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
a method for synthesizing valganciclovir hydrochloride by a microchannel reactor comprises the following steps:
s1, preparation of a material A: adding the intermediate into alcohol, adding acid while stirring, fully stirring to form a material A, conveying the material A into a module I of a microchannel reactor through a plunger pump, preheating and mixing, and then feeding into a reaction module group of the microchannel reactor, wherein the preheating temperature is 95-115 ℃, and the intermediate is (2S) -2- ((2-amino-6-oxo-1H-purine-9 (6H) -yl) methoxy) -3-hydroxypropyl 2- ((benzyloxy) carbonyl) amino) -3-methylbutyrate;
s2, preparation of material B: weighing 10% of palladium-carbon, adding the palladium-carbon into alcohol, fully stirring and mixing to form a material B, conveying the material B into a module I of a microchannel reactor through a slurry pump, preheating and mixing, and then feeding into a reaction module group of the microchannel reactor, wherein the preheating temperature is 95-115 ℃;
s3, preparation of a crude product: conveying hydrogen to a reaction module group of a microchannel reactor to react with a preheated material A and a preheated material B in the reaction module group, feeding the reaction mixture into a cooling module after reaction, collecting reaction liquid flowing out of an outlet of the cooling module, and performing post-treatment to obtain a valganciclovir hydrochloride crude product;
and S4, adding purified water and activated carbon into the crude product obtained in the step S3, stirring and filtering, adding isopropanol into the filtrate, stirring and filtering, washing a filter cake with the isopropanol, and performing vacuum drying to obtain the valganciclovir hydrochloride product.
The technical scheme of the invention is further improved as follows: the step S1 intermediate: alcohol: the mass ratio of the acid is 1:7: 0.22.
The technical scheme of the invention is further improved as follows: the alcohol in the step S1 is any one of methanol, ethanol, isopropanol and tert-butanol.
The technical scheme of the invention is further improved as follows: the alcohol in the step S2 is the same as the alcohol in the step S1, and the mass ratio of the palladium-carbon to the alcohol is 1: 15.
The technical scheme of the invention is further improved as follows: in the step S3, the flow rate of the material A is 40.0 g/min-80.0 g/min, the flow rate of the material B is 10.0 g/min-30 g/min, and the flow rate of hydrogen is 400 mL/min-500 mL/min.
The technical scheme of the invention is further improved as follows: in the step S3, the reaction temperature is 95-115 ℃, the reaction residence time is 25-35S, and the reaction pressure is 0.6-0.8 MPa.
The technical scheme of the invention is further improved as follows: the temperature of the cooling module in the step S3 is 0-40 ℃.
The technical scheme of the invention is further improved as follows: the post-processing step in step S3 is: and filtering the reaction liquid flowing out of the outlet of the cooling module to recover the catalyst, and performing reduced pressure distillation to recover the solvent to obtain a residue, wherein the temperature of the reduced pressure distillation is 35-45 ℃, the vacuum degree is less than or equal to-0.085 MPa, purified water and isopropanol are added into the residue, the residue is stirred at 0-10 ℃ for 2 hours under heat preservation, filtered, the isopropanol is used for washing a filter cake, and the crude valganciclovir hydrochloride is obtained after vacuum drying is performed for 12 hours at 40-50 ℃.
The technical scheme of the invention is further improved as follows: in the step S4, the yield of valganciclovir hydrochloride is more than 85.0%, the purity is more than 99.0%, and the palladium residue is less than 3 ppm.
Due to the adoption of the technical scheme, the invention has the technical progress that:
1) the invention provides an intrinsically safe and environment-friendly catalytic hydrogenation synthesis technology, which utilizes a microchannel reactor (also called as a microreactor) technology to complete a catalytic hydrogenation reaction to synthesize valganciclovir hydrochloride, greatly improves the reaction speed, shortens the reaction time from 12 hours to less than 30 seconds, and greatly reduces the energy consumption; meanwhile, the reactor needs to be cleaned once after running for about 24 hours in large-scale production, so that the problem of blockage of the microchannel reactor is greatly improved.
2) The invention can effectively inhibit hydrolysis byproducts, and greatly improve the yield and purity of the product; meanwhile, the palladium residue level of the product in large-scale production can be effectively reduced, palladium removing resin or kieselguhr is not needed for adsorption operation, the reaction step is omitted, the palladium residue of the product is lower than 3ppm, and the medicinal requirement is met.
3) The volume of the liquid holding volume of the invention is only dozens to hundreds of milliliters, and the potential safety hazard of hydrogen leakage, combustion and explosion can be greatly reduced under the condition of safety protection.
4) The invention has small floor area of equipment and simple operation, can realize safe and stable on-line production and post-treatment for a long time, can reduce 50 to 70 percent of operation labor, reduce the production cost and ensure the production economy.
Detailed Description
The present invention will be further described in detail with reference to the following embodiments (the microchannel reactor adopted in the present invention includes a first reaction module group and a cooling module which are sequentially connected in series):
example 1
S1, weighing 50kg of intermediate, adding the intermediate into 350kg of methanol, adding 11kg of hydrochloric acid while stirring, fully stirring to form a material A, conveying the material A into a first module of the microchannel reactor through a plunger pump, preheating, mixing and then entering a reaction module group of the microchannel reactor;
s2, weighing 8.55kg of 10% palladium-carbon, adding the 10% palladium-carbon into 128kg of methanol, fully stirring and mixing to form a material B, conveying the material B into a module I of the microchannel reactor through a slurry pump, preheating and mixing, and then feeding into a reaction module group of the microchannel reactor;
s3, conveying the hydrogen to the reaction module group of the microchannel reactor to react with the preheated material in the reaction module group, wherein: adjusting the flow rate of the plunger pump to make the flow rate of the material A be 60.0g/min, adjusting the flow rate of the slurry pump to make the flow rate of the material B be 20.0g/min, and adjusting the flow rate of the slurry pump to H2The flow rate of a gas flowmeter is 447mL/min, the reaction temperature is 100 ℃, the temperature of a cooling module is 10 ℃, the residence time of the reaction is 25.2s, the reaction pressure is 0.6MPa, the reaction liquid flowing out of an outlet of the cooling module is collected and subjected to post-treatment, the post-treatment refers to filtering and recovering a catalyst, decompressing and steaming to recover a solvent, adding 50kg of purified water into the residue, adding 589kg of isopropanol, keeping the temperature and stirring for 2h at 0-10 ℃, filtering, and washing with 39.28kg of isopropanolWashing the filter cake, and performing vacuum drying at 50 ℃ for 12h to obtain a valganciclovir hydrochloride crude product with the yield of 89.5%, the purity of 98.711% and the palladium residue of 10.54 ppm;
in step S3, the reaction is washed once every 24 hours, and the material is discharged completely during washing and then washed.
The cleaning process is as follows:
1) respectively introducing methanol to flush the microchannel reactor system through a plunger pump and a slurry pump;
2) purified water is respectively introduced through a plunger pump and a slurry pump to flush the microchannel reactor system;
3) taking nitric acid, and introducing a nitric acid solution into a reactor system through a plunger pump;
4) purified water is pumped in through a plunger pump to flush the reactor system until the pH of the effluent liquid is neutral;
5) cleaning the pump head of the plunger pump by using purified water until the pH of the effluent liquid is neutral;
6) purified water is respectively introduced into the micro-channel reactor system through a plunger pump and a slurry pump to flush the micro-channel reactor system.
S4, taking 25kg of the crude product obtained in the previous step, adding 50kg of purified water and 1.25kg of activated carbon, stirring for 0.5h, filtering, adding 275kg of isopropanol into the filtrate, stirring at 0-10 ℃ for 2h under heat preservation, filtering, washing the filter cake with 19.5kg of isopropanol, and vacuum drying at 50 ℃ for 12h to obtain valganciclovir hydrochloride, wherein the yield is 85.5%, the purity is 99.245%, and the palladium residue is 2.45 ppm.
Example 2 (ethanol)
S1, weighing 50kg of intermediate, adding the intermediate into 350kg of ethanol, adding 11kg of hydrochloric acid while stirring, fully stirring to form a material A, conveying the material A into a first module of the microchannel reactor through a plunger pump, preheating, mixing and then entering a reaction module group of the microchannel reactor;
s2, weighing 8.55kg of 10% palladium-carbon, adding the 10% palladium-carbon into 128kg of ethanol, fully stirring and mixing to form a material B, conveying the material B into a module I of the microchannel reactor through a slurry pump, preheating and mixing, and then feeding into a reaction module group of the microchannel reactor;
s3, conveying the hydrogen to the reaction module group of the micro-channel reactor and the processThe preheated materials react in the reaction module group, wherein: adjusting the flow rate of the plunger pump to make the flow rate of the material A be 60.0g/min, adjusting the flow rate of the slurry pump to make the flow rate of the material B be 20.0g/min, and adjusting the flow rate of the slurry pump to H2The flow rate of a gas flowmeter is 447mL/min, the reaction temperature is 100 ℃, the temperature of a cooling module is 10 ℃, the residence time of the reaction is 25s, the reaction pressure is 0.6MPa, the reaction liquid flowing out of the outlet of the cooling module is collected and subjected to post-treatment, the post-treatment refers to filtering and recovering a catalyst, decompressing and evaporating to recover a solvent, after 50kg of purified water is added into residues, 589kg of isopropanol is added, the mixture is stirred for 2h at the temperature of 0-10 ℃, the mixture is filtered, 39.28kg of isopropanol is used for washing filter cakes, and after vacuum drying is carried out for 12h at the temperature of 50 ℃, crude valganciclovir hydrochloride is obtained, the yield is 89.1%, the purity is 98.924%, and the palladium residue is 11.22 ppm;
in step S3, the reaction was washed once every 24 hours, and the material was discharged completely during washing, followed by washing as in example 1.
S4, taking 25kg of the crude product obtained in the previous step, adding 50kg of purified water and 1.25kg of activated carbon, stirring for 0.5h, filtering, adding 275kg of isopropanol into the filtrate, stirring for 2h at 0-10 ℃ under a heat preservation condition, filtering, washing a filter cake with 19.5kg of isopropanol, and drying for 12h in vacuum at 50 ℃ to obtain valganciclovir hydrochloride, wherein the yield is 87.5%, the purity is 99.178%, and the palladium residue is 1.94 ppm.
Example 3 (different reaction temperatures)
S1, weighing 50kg of intermediate, adding the intermediate into 350kg of methanol, adding 11kg of hydrochloric acid while stirring, fully stirring to form a material A, conveying the material A into a first module of the microchannel reactor through a plunger pump, preheating, mixing and then entering a reaction module group of the microchannel reactor;
s2, weighing 8.55kg of 10% palladium carbon, adding the palladium carbon into 128kg of methanol, fully stirring and mixing to form a material B, conveying the material B into a module I of the microchannel reactor through a slurry pump, preheating and mixing, and then feeding into a reaction module group of the microchannel reactor;
s3, conveying the hydrogen to the reaction module group of the microchannel reactor to react with the preheated material in the reaction module group, wherein: the flow rate of the plunger pump is adjusted to make the flow rate of the material A be 60.0g/min,adjusting the flow rate of the slurry pump to make the flow rate of the material B be 20.0g/min, and adjusting H2The flow rate of a gas flowmeter is 447mL/min, the reaction temperature is 110 ℃, the temperature of a cooling module is 10 ℃, the residence time of the reaction is 25s, the reaction pressure is 0.6MPa, the reaction liquid flowing out of the outlet of the cooling module is collected and subjected to post-treatment, the post-treatment refers to filtering and recovering a catalyst, decompressing and evaporating to recover a solvent, after 50kg of purified water is added into residues, 589kg of isopropanol is added, the mixture is stirred for 2h at the temperature of 0-10 ℃, the mixture is filtered, 39.28kg of isopropanol is used for washing filter cakes, and after vacuum drying is carried out for 12h at the temperature of 50 ℃, crude valganciclovir hydrochloride is obtained, the yield is 87.5%, the purity is 99.014%, and the palladium residue is 9.67 ppm;
in step S3, the reaction was washed once every 24 hours, and the material was discharged completely during washing, followed by washing as in example 1.
S4, taking 25kg of the crude product obtained in the previous step, adding 50kg of purified water and 1.25kg of activated carbon, stirring for 0.5h, filtering, adding 275kg of isopropanol into the filtrate, stirring at 0-10 ℃ for 2h under heat preservation, filtering, washing the filter cake with 19.5kg of isopropanol, and vacuum drying at 50 ℃ for 12h to obtain valganciclovir hydrochloride, wherein the yield is 86.3%, the purity is 99.246%, and the palladium residue is 1.90 ppm.
Comparative example 1:
s1, weighing 50kg of intermediate, adding the intermediate into 500kg of methanol, adding 11kg of hydrochloric acid and 8.55kg of 10% palladium carbon under stirring, fully stirring to form a material A, conveying the material A into a first module of the microchannel reactor through a slurry pump, preheating, mixing and then entering a reaction module group of the microchannel reactor.
S2, conveying the hydrogen to the reaction module group of the microchannel reactor to react with the preheated material in the reaction module group, wherein: adjusting the flow rate of the slurry pump to make the flow rate of the material A be 80.0g/min, and adjusting H2The flow rate of the gas flowmeter is 447mL/min, the molar ratio of the intermediate to hydrogen is 1:1.3, the reaction temperature is 100 ℃, the temperature of the cooling module is 10 ℃, the residence time of the reaction is 28s, the reaction pressure is 0.6MPa, the reaction liquid flowing out of the outlet of the cooling module is collected for post-treatment, the post-treatment refers to filtration and recovery of the catalyst, reduced pressure evaporation and recovery of the solvent, 50kg of purified residue is addedAdding 589kg of isopropanol into water, keeping the temperature of 0-10 ℃, stirring for 2h, filtering, washing a filter cake with 39.28kg of isopropanol, and drying in vacuum at 50 ℃ for 12h to obtain a valganciclovir hydrochloride crude product with the yield of 88.1%, the purity of 96.532% and the palladium residue of 587.48 ppm.
In step S2, the reaction was washed once every 2 hours, and the material was discharged completely during washing, followed by washing as in example 1.
S3, taking 25kg of the crude product obtained in the previous step, adding 50kg of purified water and 1.25kg of activated carbon, stirring for 0.5h, filtering, adding 275kg of isopropanol into the filtrate, stirring for 2h at 0-10 ℃ under a heat preservation condition, filtering, washing a filter cake with 19.5kg of isopropanol, and drying for 12h in vacuum at 50 ℃ to obtain valganciclovir hydrochloride, wherein the yield is 86.3%, the purity is 97.912%, and the palladium residue is 178.28 ppm.
And (3) comparing experimental data:
table 1 crude data
| Crude data | Example 1 | Example 2 | Example 3 | Comparative example 1 |
| Yield (%) | 89.5 | 89.1 | 87.5 | 88.1 |
| Impurity A (%) | 0.383 | 0.374 | 0.296 | 1.371 |
| Single impurity (%) | 0.189 | 0.174 | 0.154 | 0.385 |
| Purity (%) | 98.711 | 98.924 | 99.014 | 96.532 |
| Residual Palladium (ppm) | 10.54 | 11.22 | 9.61 | 587.48 |
TABLE 2 data on the finished product
| Data of finished product | Example 1 | Example 2 | Example 3 | Comparative example 1 |
| Yield (%) | 85.5 | 87.5 | 86.3 | 86.3 |
| Impurity A (%) | 0.431 | 0.430 | 0.390 | 1.481 |
| Single impurity (%) | 0.046 | 0.023 | 0.041 | 0.056 |
| Purity (%) | 99.245 | 99.178 | 99.246 | 97.912 |
| Residual Palladium (ppm) | 2.45 | 1.94 | 1.90 | 178.28 |
Claims (9)
1. A method for synthesizing valganciclovir hydrochloride by a microchannel reactor comprises the following steps:
s1, preparation of a material A: adding the intermediate into alcohol, adding acid while stirring, fully stirring to form a material A, conveying the material A into a module I of a microchannel reactor through a plunger pump, preheating and mixing, and then feeding into a reaction module group of the microchannel reactor, wherein the preheating temperature is 95-115 ℃, and the intermediate is (2S) -2- ((2-amino-6-oxo-1H-purine-9 (6H) -yl) methoxy) -3-hydroxypropyl 2- ((benzyloxy) carbonyl) amino) -3-methylbutyrate;
s2, preparation of material B: weighing 10% of palladium-carbon, adding the palladium-carbon into alcohol, fully stirring and mixing to form a material B, conveying the material B into a module I of a microchannel reactor through a slurry pump, preheating and mixing, and then feeding into a reaction module group of the microchannel reactor, wherein the preheating temperature is 95-115 ℃;
s3, preparation of a crude product: conveying hydrogen to a reaction module group of a microchannel reactor to react with a preheated material A and a preheated material B in the reaction module group, feeding the reaction mixture into a cooling module after reaction, collecting reaction liquid flowing out of an outlet of the cooling module, and performing post-treatment to obtain a valganciclovir hydrochloride crude product;
and S4, adding purified water and activated carbon into the crude product obtained in the step S3, stirring and filtering, adding isopropanol into the filtrate, stirring and filtering, washing a filter cake with the isopropanol, and performing vacuum drying to obtain the valganciclovir hydrochloride product.
2. The method for synthesizing valganciclovir hydrochloride by using the microchannel reactor as claimed in claim 1, wherein the step S1 intermediate is as follows: alcohol: the mass ratio of the acid is 1:7: 0.22.
3. The method for synthesizing valganciclovir hydrochloride by using a microchannel reactor as claimed in claim 2, wherein the alcohol in step S1 is any one of methanol, ethanol, isopropanol and tert-butanol.
4. The method for synthesizing valganciclovir hydrochloride by using the microchannel reactor as claimed in claim 3, wherein the alcohol in step S2 is the same as the alcohol in step S1, and the mass ratio of palladium on carbon to the alcohol is 1: 15.
5. The method for synthesizing valganciclovir hydrochloride by using the microchannel reactor as claimed in claim 1, wherein the flow rate of material A in step S3 is 40.0 g/min-80.0 g/min, the flow rate of material B is 10.0 g/min-30 g/min, and the flow rate of hydrogen is 400 mL/min-500 mL/min.
6. The method for synthesizing valganciclovir hydrochloride by using the microchannel reactor as claimed in claim 5, wherein the reaction temperature in step S3 is 95-115 ℃, the reaction residence time is 25-35S, and the reaction pressure is 0.6-0.8 MPa.
7. The method for synthesizing valganciclovir hydrochloride by using the microchannel reactor as claimed in claim 1, wherein the temperature of the cooling module in step S3 is 0 ℃ to 40 ℃.
8. The method for synthesizing valganciclovir hydrochloride by using the microchannel reactor as claimed in claim 1, wherein the post-processing step in step S3 is: and filtering the reaction liquid flowing out of the outlet of the cooling module to recover the catalyst, and performing reduced pressure distillation to recover the solvent to obtain a residue, wherein the temperature of the reduced pressure distillation is 35-45 ℃, the vacuum degree is less than or equal to-0.085 MPa, purified water and isopropanol are added into the residue, the residue is stirred at the temperature of 0-10 ℃ for 2 hours under the condition of heat preservation, filtering, washing a filter cake with the isopropanol, and performing vacuum drying at the temperature of 40-50 ℃ for 12 hours to obtain a valganciclovir hydrochloride crude product.
9. The method for synthesizing valganciclovir hydrochloride by using the microchannel reactor as claimed in claim 1, wherein the yield of valganciclovir hydrochloride in step S4 is greater than 85.0%, the purity is greater than 99.0%, and the palladium residue is less than 3 ppm.
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