CN113880838B - Method for synthesizing valganciclovir hydrochloride by micro-channel reactor - Google Patents
Method for synthesizing valganciclovir hydrochloride by micro-channel reactor Download PDFInfo
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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 40
- 229960004983 valganciclovir hydrochloride Drugs 0.000 title claims abstract description 40
- 238000000034 method Methods 0.000 title claims abstract description 22
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 13
- 239000000463 material Substances 0.000 claims abstract description 65
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 26
- 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
- 238000011031 large-scale manufacturing process Methods 0.000 claims abstract description 7
- 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 60
- 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 25
- 238000001816 cooling Methods 0.000 claims description 19
- 239000012043 crude product Substances 0.000 claims description 19
- 238000002156 mixing Methods 0.000 claims description 19
- 239000008213 purified water Substances 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 239000002002 slurry Substances 0.000 claims description 14
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 13
- 239000012065 filter cake Substances 0.000 claims description 13
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 12
- 238000001291 vacuum drying Methods 0.000 claims description 10
- 239000003054 catalyst Substances 0.000 claims description 9
- 239000012295 chemical reaction liquid Substances 0.000 claims description 9
- 238000005406 washing Methods 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
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 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
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 3
- -1 (2S) -2- ((2-amino-6-oxo-1H-purin-9 (6H) -yl) methoxy) -3-hydroxypropyl Chemical group 0.000 claims description 2
- 239000007795 chemical reaction product Substances 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 238000005984 hydrogenation reaction Methods 0.000 abstract description 2
- 238000004140 cleaning Methods 0.000 description 17
- 239000000047 product Substances 0.000 description 15
- 230000001105 regulatory effect Effects 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 238000004519 manufacturing process Methods 0.000 description 8
- 239000012535 impurity Substances 0.000 description 5
- 239000007789 gas Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 239000003814 drug Substances 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
- 229910052763 palladium Inorganic materials 0.000 description 3
- 230000035484 reaction time Effects 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
- 239000007788 liquid Substances 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
- 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
- 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
- 230000000903 blocking effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000002485 combustion reaction Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000001419 dependent effect Effects 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
- 238000004880 explosion Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 238000011010 flushing procedure Methods 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
- 239000000203 mixture Substances 0.000 description 1
- 238000000465 moulding Methods 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
- 238000012805 post-processing Methods 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 238000000197 pyrolysis Methods 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
- 238000004904 shortening Methods 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
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
Abstract
The invention discloses a method for synthesizing valganciclovir hydrochloride by a micro-channel reactor, which comprises the steps of respectively preparing a material A and a material B, adding the materials A and the material B into the micro-channel reactor, and then introducing hydrogen for hydrogenation reaction to obtain valganciclovir hydrochloride; meanwhile, palladium residue in large-scale production can be reduced, and the product yield and purity are improved.
Description
Technical Field
The invention relates to a method for synthesizing valganciclovir hydrochloride by a micro-channel reactor, belonging to the technical field of medicines.
Background
Valganciclovir hydrochloride is an oral anti-Cell (CMV) infection drug developed by the company roche, switzerland, approved for sale by the FDA in the united states of america, month 5 of 2001. Clinically used for treating acute retinitis of patients with acquired immunodeficiency syndrome caused by CMV infection; preventing and treating CMV infection of organ transplants. The product is a prodrug of ganciclovir, and is rapidly hydrolyzed into ganciclovir by esterase in intestinal tracts and liver cells after oral administration, so that the drug effect is exerted, the oral absorption bioavailability of the product is 10 times that of ganciclovir, the toxicity is greatly reduced, and the product has a broad market prospect. Valganciclovir hydrochloride belongs to a clinical urgent need medicine in China, but no domestic variety is marketed, the valganciclovir hydrochloride is completely dependent on import, the valganciclovir hydrochloride is expensive, and the economic burden of patients is heavy.
Valganciclovir hydrochloride has a complex structure and high synthesis difficulty, the synthesis of valganciclovir hydrochloride is researched in patents US5840891, WO9727194, US5700936, CN107163050 and the like, different routes are optimized at different angles, but all reported routes relate to a key step, benzyloxycarbonyl protecting groups are required to be removed, and the chemical reaction formula is as follows:
currently, there are two main methods for deprotection of N-benzyloxycarbonyl (Cbz): 1) Acidolysis and pyrolysis: generally, hydrobromic acid/acetic acid systems are used, and when the Cbz protecting group is removed, the product is difficult to avoid and the potentially genotoxic impurity benzyl bromide generated by decomposition generates a few side reactions and is difficult to remove. 2) Catalytic hydrogenolysis: the method has the advantages that cheap and environment-friendly hydrogen is used as a reducing agent, palladium carbon, raney nickel and other heavy metal catalysts are reduced to obtain a target product, and the method is a main method for synthesizing valganciclovir hydrochloride at present, but the flammable and explosive properties of the hydrogen cause great potential safety hazard in the large-scale production process because the reaction is usually carried out under high pressure, and the operation difficulty is great; in addition, the reaction can be completed under the catalysis of noble metals such as Pd, ni and the like, and the catalyst cannot be dissolved in a reaction system under the general condition, 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 raw materials are difficult to ensure complete reaction, the mixing effect of a conventional hydrogenation kettle is poor after amplification, the reaction time is greatly increased, and the product purity and the yield are low.
In summary, the existing main methods for synthesizing valganciclovir hydrochloride have the problems of heavy environmental pollution, poor safety, high operation difficulty, low product yield, poor purity and the like.
In order to solve the above problems, a microchannel reactor is considered because the microchannel reactor can shorten the reaction time of a general chemical reaction and can solve the problems of releasing a large amount of heat and a large amount of byproducts 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 the material A, then entering a reaction module group of the microchannel reactor, conveying hydrogen into the reaction module group of the microchannel reactor, reacting the reaction module group of the microchannel reactor with the preheated material in the reaction module group, wherein the reaction temperature is 100 ℃, the reaction residence time is 28s, the reaction pressure is 0.6MPa, collecting the reaction liquid flowing out of 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 the catalyst, distilling and recovering the solvent under reduced pressure, adding purified water and isopropanol into residues, and vacuum drying at 50 ℃ for 12 hours to obtain valganciclovir hydrochloride crude products, wherein the yield is more than 85.0%, the purity is more than 98.5%, and the palladium residue is less than 15ppm.
Adding purified water and active carbon into the crude product obtained in the previous step, stirring for 0.5h, filtering, adding isopropanol into the filtrate, keeping the temperature between 0 and 10 ℃ and stirring for 2h, filtering, washing a filter cake with the isopropanol, and vacuum drying for 12h at 50 ℃ to obtain valganciclovir hydrochloride Wei Chunpin, wherein the yield is more than 85.0%, the purity is more than 99.0%, and the palladium residue is less than 3ppm.
The laboratory effect is good and scale production is carried out, but after the scale production is enlarged, not only the blockage problem is serious and the production efficiency is affected, but also the palladium residue is greatly increased after detection, the crude product palladium residue is 587ppm, and the pure product palladium residue is 178ppm. The adding amount of the intermediate in the laboratory is 100g, the material flow is completed only for 10-20min, the adding amount of the intermediate is 50kg during large-scale production, the material flow is completed for 80-170h, the reaction needs to be cleaned every about 2 hours, the material needs to be completely discharged during cleaning, then strong acid is introduced for cleaning, and the cleaning time needs 5-6 hours, so that 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 a micro-channel reactor, which can greatly improve the blocking problem of the micro-channel reactor in large-scale production; meanwhile, palladium residue in the molding production can be reduced, and the product yield and purity are improved.
In order to solve the technical problems, the invention adopts the following technical scheme:
a method for synthesizing valganciclovir hydrochloride by a micro-channel reactor, which comprises the following steps:
s1, preparing a material A: adding the intermediate into alcohol, adding acid under stirring, fully stirring to form a material A, conveying the material A into a first module of a microchannel reactor through a plunger pump, preheating and mixing the material A, and then entering 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-purin-9 (6H) -yl) methoxy) -3-hydroxypropyl 2- ((benzyloxy) carbonyl) amino) -3-methylbutyrate;
s2, preparing a material B: weighing 10% palladium-carbon, adding the palladium-carbon into alcohol, fully stirring and mixing to form a material B, conveying the material B into a first module of a microchannel reactor through a slurry pump, preheating and mixing, and then entering a reaction module group of the microchannel reactor, wherein the preheating temperature is 95-115 ℃;
s3, preparing a crude product: the hydrogen is conveyed to a reaction module group of the microchannel reactor, the preheated material A and the preheated material B react in the reaction module group, the reaction products enter a cooling module after reaction, the reaction liquid flowing out of an outlet of the cooling module is collected, and a valganciclovir hydrochloride crude product is obtained after post treatment;
s4, adding the crude product obtained in the step S3 into purified water and activated carbon, stirring, filtering, adding isopropanol into the filtrate, stirring, filtering, washing a filter cake with isopropanol, and 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, isopropyl alcohol and tert-butyl alcohol.
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 palladium-carbon to the alcohol is 1:15.
The technical scheme of the invention is further improved as follows: the flow rate of the material A in the step S3 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 the hydrogen is 400 mL/min-500 mL/min.
The technical scheme of the invention is further improved as follows: the reaction temperature in the step S3 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 the step S3 is as follows: and filtering the reaction liquid flowing out of the outlet of the cooling module to recover the catalyst, distilling under reduced pressure to recover the solvent to obtain residues, distilling under reduced pressure at the temperature of 35-45 ℃ and the vacuum degree of less than or equal to-0.085 MPa, adding purified water and isopropanol into the residues, stirring at the temperature of 0-10 ℃ for 2h, filtering, washing the filter cake with isopropanol, and drying at the temperature of 40-50 ℃ for 12h in vacuum to obtain a valganciclovir hydrochloride crude product.
The technical scheme of the invention is further improved as follows: in the step S4, valganciclovir hydrochloride Wei Shoulv is more than 85.0%, the purity is more than 99.0%, and the palladium residue is less than 3ppm.
By adopting the technical scheme, the invention has the following technical progress:
1) The invention provides an intrinsically safe and environment-friendly catalytic hydrogenation synthesis technology, which utilizes a micro-channel reactor (also called a micro-reactor) technology to complete a catalytic hydrogenation reaction to synthesize valganciclovir hydrochloride, thereby greatly improving the reaction speed, shortening the reaction time from 12 hours to less than 30 seconds and greatly reducing the energy consumption; meanwhile, the micro-channel reactor needs to be cleaned once when the micro-channel reactor is operated for about 24 hours in large-scale production, so that the problem of blockage of the micro-channel reactor is greatly solved.
2) The invention can effectively inhibit hydrolysis byproducts, and greatly improve the yield and purity of the product; meanwhile, the palladium residual level of the product in large-scale production can be effectively reduced, the adsorption operation is not required to be carried out by adopting palladium-removing resin or diatomite, the reaction step is omitted, the palladium residual of the product is lower than 3ppm, and the medicinal requirement is met.
3) The invention has the liquid volume of tens to hundreds milliliters, and can greatly reduce the potential safety hazard of hydrogen leakage combustion explosion under the condition of safety protection.
4) The equipment disclosed by the invention has the advantages of small occupied area, simplicity in operation, capability of realizing long-time safe and stable online production and post-treatment, capability of reducing the operation labor by 50% to 70%, capability of reducing the production cost and capability of ensuring the production economy.
Detailed Description
The present invention will be described in further detail with reference to the following examples (the microchannel reactor used in the present invention includes a reaction module group and a cooling module which are sequentially connected in series):
example 1
S1, weighing 50kg of intermediate, adding into 350kg of methanol, adding 11kg of hydrochloric acid under stirring, fully stirring to form a material A, conveying the material A into a first module of a microchannel reactor through a plunger pump, preheating and mixing, and then entering a reaction module group of the microchannel reactor;
s2, weighing 8.55kg of 10% palladium-carbon, adding the weighed 8.55kg of 10% palladium-carbon into 128kg of methanol, fully stirring and mixing to form a material B, conveying the material B into a first module of the microchannel reactor through a slurry pump, preheating and mixing, and then entering a reaction module group of the microchannel reactor;
s3, conveying hydrogen to a 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 regulated to enable the flow rate of the material A to be 60.0g/min, the flow rate of the slurry pump is regulated to enable the flow rate of the material B to be 20.0g/min, and the flow rate of the material H is regulated 2 The flow rate of the gas flowmeter is 447mL/min, the reaction temperature is 100 ℃, the temperature of the 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 the outlet of the cooling module is collected for post-treatment, the post-treatment refers to filtering and recovering the catalyst, the solvent is recovered by decompression and distillation, after 50kg of purified water is added into the residue, 589kg of isopropanol is added, the temperature is kept between 0 and 10 ℃ and stirred for 2 hours, the filtration is carried out, 39.28kg of isopropanol washes the filter cake, and the vacuum drying is carried out for 12 hours at 50 ℃ to obtain valganciclovir hydrochloride crude product, the yield is 89.5%, the purity is 98.711%, and the palladium residue is 10.54ppm;
wherein, step S3 reaction is carried out for about 24 hours for cleaning, and materials are completely discharged during cleaning, and then the cleaning is carried out.
The cleaning process is as follows:
1) Respectively introducing methanol to wash the micro-channel reactor system through a plunger pump and a slurry pump;
2) Respectively introducing purified water to flush the micro-channel reactor system through a plunger pump and a slurry pump;
3) Taking nitric acid, and introducing a nitric acid solution into a reactor system through a plunger pump;
4) Introducing purified water to flush the reactor system through a plunger pump until the pH of the effluent is neutral;
5) Cleaning the pump head of the plunger pump by using purified water until the pH value of effluent liquid is neutral;
6) And flushing the micro-channel reactor system by respectively introducing purified water through a plunger pump and a slurry pump.
S4, taking 25kg of 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 ℃, filtering, washing a filter cake with 19.5kg of isopropanol, and vacuum drying for 12h at 50 ℃ to obtain valganciclovir hydrochloride, wherein the yield is 85.5%, the purity is 99.245%, and the palladium residue is 2.45ppm.
Example 2 (ethanol)
S1, weighing 50kg of intermediate, adding into 350kg of ethanol, adding 11kg of hydrochloric acid under stirring, fully stirring to form a material A, conveying the material A into a first module of a microchannel reactor through a plunger pump, preheating and mixing, and then entering a reaction module group of the microchannel reactor;
s2, weighing 8.55kg of 10% palladium-carbon, adding the weighed 8.55kg of 10% palladium-carbon into 128kg of ethanol, fully stirring and mixing to form a material B, conveying the material B into a first module of the microchannel reactor through a slurry pump, preheating and mixing, and then entering a reaction module group of the microchannel reactor;
s3, conveying hydrogen to a 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 regulated to enable the flow rate of the material A to be 60.0g/min, the flow rate of the slurry pump is regulated to enable the flow rate of the material B to be 20.0g/min, and the flow rate of the material H is regulated 2 The flow rate of the gas flowmeter is 447mL/min, the reaction temperature is 100 ℃, the temperature of the cooling module is 10 ℃, the reaction residence time is 25s, the reaction pressure is 0.6MPa, the reaction liquid flowing out of the outlet of the cooling module is collected, the post-treatment is carried out, the catalyst is recovered by filtration, the solvent is recovered by reduced pressure distillation, 50kg of purified water is added into the residue, 589kg of isopropanol is added, the temperature is kept at 0-10 ℃ and stirred for 2h, the filtration is carried out, 39.28kg of isopropanol washes the filter cake, the vacuum drying is carried out for 12h at 50 ℃ to obtain valganciclovir hydrochloride crude product, the yield is 89.1%, the purity is 98.924%, and the palladium residue is 11.22ppm;
wherein, step S3 is carried out for about 24 hours, the materials are all discharged during the cleaning, and then the cleaning is carried out, and the cleaning process is as in example 1.
S4, taking 25kg of 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 ℃, filtering, washing a filter cake with 19.5kg of isopropanol, and vacuum drying for 12h at 50 ℃ to obtain valganciclovir hydrochloride, wherein the yield is 87.5%, the purity is 99.178%, and the palladium residue is 1.94ppm.
Example 3 (different reaction temperatures)
S1, weighing 50kg of intermediate, adding into 350kg of methanol, adding 11kg of hydrochloric acid under stirring, fully stirring to form a material A, conveying the material A into a first module of a microchannel reactor through a plunger pump, preheating and mixing, and then entering a reaction module group of the microchannel reactor;
s2, weighing 8.55kg of 10% palladium on charcoal, adding into 128kg of methanol, fully stirring and mixing to form a material B, conveying the material B into a first module of the microchannel reactor through a slurry pump, preheating and mixing, and then entering a reaction module group of the microchannel reactor;
s3, conveying hydrogen to a 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 regulated to enable the flow rate of the material A to be 60.0g/min, the flow rate of the slurry pump is regulated to enable the flow rate of the material B to be 20.0g/min, and the flow rate of the material H is regulated 2 The flow rate of the gas flowmeter is 447mL/min, the reaction temperature is 110 ℃, the temperature of the 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 for post-treatment, the post-treatment refers to filtering and recovering the catalyst, the solvent is recovered by reduced pressure distillation, 50kg of purified water is added into the residue, 589kg of isopropanol is added into the residue, the mixture is stirred for 2h at 0-10 ℃ under heat preservation, the residue is filtered, 39.28kg of isopropanol washes the filter cake, the residue is dried for 12h under 50 ℃ under vacuum to obtain valganciclovir hydrochloride crude product, the yield is 87.5%, the purity is 99.014%, and the palladium residue is 9.67ppm;
wherein, step S3 is carried out for about 24 hours, the materials are all discharged during the cleaning, and then the cleaning is carried out, and the cleaning process is as in example 1.
S4, taking 25kg of 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 ℃, filtering, washing a filter cake with 19.5kg of isopropanol, and drying in vacuum for 12h at 50 ℃ to obtain valganciclovir hydrochloride, wherein the yield is 86.3%, the purity is 99.246%, and the palladium residue is 1.90ppm.
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 on charcoal 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, and then entering a reaction module group of the microchannel reactor.
S2, conveying hydrogen to a reaction module group of the microchannel reactor to react with the preheated material in the reaction module group, wherein: regulating the flow rate of the slurry pump to enable the flow rate of the material A to be 80.0g/min, and regulating H 2 The flow rate of the gas flowmeter is 447mL/min, the molar ratio of the intermediate to the hydrogen is 1:1.3, the reaction temperature is 100 ℃, the temperature of the cooling module is 10 ℃, the reaction residence time is 28s, 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 is to filter and recycle the catalyst, the solvent is distilled and recycled under reduced pressure, after 50kg of purified water is added into the residue, 589kg of isopropanol is added, the temperature is kept between 0 and 10 ℃ and stirred for 2 hours, the filtration is carried out, 39.28kg of isopropanol washes the filter cake, and the valganciclovir hydrochloride crude product is obtained after vacuum drying at 50 ℃ for 12 hours, the yield is 88.1%, the purity is 96.532%, and the palladium residue is 587.48ppm.
Wherein, step S2 reaction is carried out for about 2 hours, the materials are all discharged during the cleaning, and then the cleaning is carried out, and the cleaning process is as in example 1.
S3, taking 25kg of 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 ℃, filtering, washing a filter cake with 19.5kg of isopropanol, and vacuum drying for 12h at 50 ℃ to obtain valganciclovir hydrochloride, wherein the yield is 86.3%, the purity is 97.912%, and the palladium residue is 178.28ppm.
Comparison of 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 |
| Palladium residue (ppm) | 10.54 | 11.22 | 9.61 | 587.48 |
TABLE 2 data on finished products
| Product data | 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 |
| Palladium residue (ppm) | 2.45 | 1.94 | 1.90 | 178.28 |
Claims (6)
1. A method for synthesizing valganciclovir hydrochloride by a micro-channel reactor, which comprises the following steps:
s1, preparing a material A: adding the intermediate into alcohol, adding acid under stirring, fully stirring to form a material A, conveying the material A into a first module of a microchannel reactor through a plunger pump, preheating and mixing the material A, and then entering 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-purin-9 (6H) -yl) methoxy) -3-hydroxypropyl 2- ((benzyloxy) carbonyl) amino) -3-methylbutyrate;
s2, preparing a material B: weighing 10% palladium-carbon, adding the palladium-carbon into alcohol, fully stirring and mixing to form a material B, conveying the material B into a first module of a microchannel reactor through a slurry pump, preheating and mixing, and then entering a reaction module group of the microchannel reactor, wherein the preheating temperature is 95-115 ℃;
s3, preparing a crude product: the hydrogen is conveyed to a reaction module group of the microchannel reactor, the preheated material A and the preheated material B react in the reaction module group, the reaction products enter a cooling module after reaction, the reaction liquid flowing out of an outlet of the cooling module is collected, and a valganciclovir hydrochloride crude product is obtained after post treatment;
the flow rate of the material A in the step S3 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 the hydrogen is 400 mL/min-500 mL/min;
the reaction temperature in the step S3 is 95-115 ℃, the reaction residence time is 25-35S, and the reaction pressure is 0.6-0.8 MPa;
s4, adding the crude product obtained in the step S3 into purified water and activated carbon, stirring, filtering, adding isopropanol into the filtrate, stirring, filtering, washing a filter cake with isopropanol, and vacuum drying to obtain valganciclovir hydrochloride;
in the step S4, valganciclovir hydrochloride Wei Shoulv is more than 85.0%, the purity is more than 99.0%, palladium residue is less than 3ppm, and meanwhile, the reaction kettle needs to be cleaned once from about 24 hours during large-scale production, so that the problem of blockage of a microchannel reactor is greatly solved.
2. A process for the synthesis of valganciclovir hydrochloride in a microchannel reactor according to claim 1, wherein step S1 is intermediate: alcohol: the mass ratio of the acid is 1:7:0.22.
3. A method for synthesizing valganciclovir hydrochloride in a microchannel reactor according to claim 2, wherein the alcohol in step S1 is any one of methanol, ethanol, isopropyl alcohol and tert-butyl alcohol.
4. A method for synthesizing valganciclovir hydrochloride in a microchannel reactor according to claim 3, wherein the alcohol in step S2 is the same as the alcohol in step S1, and the mass ratio of palladium-carbon to alcohol is 1:15.
5. The method for synthesizing valganciclovir hydrochloride by using a microchannel reactor according to claim 1, wherein the temperature of the cooling module in the step S3 is 0 ℃ to 40 ℃.
6. A method for synthesizing valganciclovir hydrochloride by using a micro-channel reactor according to claim 1, wherein the post-treatment step in step S3 is as follows: and filtering the reaction liquid flowing out of the outlet of the cooling module to recover the catalyst, distilling under reduced pressure to recover the solvent to obtain residues, distilling under reduced pressure at the temperature of 35-45 ℃ and the vacuum degree of less than or equal to-0.085 MPa, adding purified water and isopropanol into the residues, stirring at the temperature of 0-10 ℃ for 2 hours, filtering, washing the filter cake with the isopropanol, and drying at the temperature of 40-50 ℃ in vacuum for 12 hours to obtain a valganciclovir hydrochloride crude product.
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