CN113880776B - Preparation method of rituximab intermediate - Google Patents
Preparation method of rituximab intermediate Download PDFInfo
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- CN113880776B CN113880776B CN202111355333.2A CN202111355333A CN113880776B CN 113880776 B CN113880776 B CN 113880776B CN 202111355333 A CN202111355333 A CN 202111355333A CN 113880776 B CN113880776 B CN 113880776B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 229960004641 rituximab Drugs 0.000 title claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 59
- 150000001875 compounds Chemical class 0.000 claims abstract description 47
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 30
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000002904 solvent Substances 0.000 claims abstract description 20
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 19
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 18
- FTZQXOJYPFINKJ-UHFFFAOYSA-N 2-fluoroaniline Chemical compound NC1=CC=CC=C1F FTZQXOJYPFINKJ-UHFFFAOYSA-N 0.000 claims abstract description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000007789 gas Substances 0.000 claims abstract description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229930040373 Paraformaldehyde Natural products 0.000 claims abstract description 9
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims abstract description 9
- 150000007530 organic bases Chemical class 0.000 claims abstract description 9
- 229920002866 paraformaldehyde Polymers 0.000 claims abstract description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 9
- RKUSRLUGUVDNKP-UHFFFAOYSA-N 2-methoxy-5-(trifluoromethyl)aniline Chemical compound COC1=CC=C(C(F)(F)F)C=C1N RKUSRLUGUVDNKP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000003054 catalyst Substances 0.000 claims abstract description 8
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 claims abstract description 8
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000002253 acid Substances 0.000 claims abstract description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 17
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 16
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 14
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 12
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 12
- 230000035484 reaction time Effects 0.000 claims description 10
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 9
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical group CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 8
- VEARAJMPQAVJAL-UHFFFAOYSA-N acetic acid trimethyl phosphate Chemical compound C(C)(=O)O.P(=O)(OC)(OC)OC VEARAJMPQAVJAL-UHFFFAOYSA-N 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 7
- 238000007098 aminolysis reaction Methods 0.000 claims description 6
- 238000007363 ring formation reaction Methods 0.000 claims description 6
- 230000002378 acidificating effect Effects 0.000 claims description 4
- 230000006229 amino acid addition Effects 0.000 claims description 4
- 238000007265 chloromethylation reaction Methods 0.000 claims description 4
- 229940043279 diisopropylamine Drugs 0.000 claims description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 17
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 abstract description 5
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 4
- 231100000086 high toxicity Toxicity 0.000 abstract description 2
- WVLBCYQITXONBZ-UHFFFAOYSA-N trimethyl phosphate Chemical compound COP(=O)(OC)OC WVLBCYQITXONBZ-UHFFFAOYSA-N 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 54
- 239000007787 solid Substances 0.000 description 24
- 238000004128 high performance liquid chromatography Methods 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 238000010992 reflux Methods 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000007791 liquid phase Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 238000005070 sampling Methods 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- ZOBYBACEALCILX-UHFFFAOYSA-N methyl 2-[8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-2-oxo-1,4-dihydroquinazolin-4-yl]acetate Chemical compound O=C1NC2=C(F)C=CC=C2C(CC(=O)OC)N1C1=CC(C(F)(F)F)=CC=C1OC ZOBYBACEALCILX-UHFFFAOYSA-N 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 238000004321 preservation Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- HIFJUMGIHIZEPX-UHFFFAOYSA-N sulfuric acid;sulfur trioxide Chemical compound O=S(=O)=O.OS(O)(=O)=O HIFJUMGIHIZEPX-UHFFFAOYSA-N 0.000 description 3
- ALZFPYUPNVLVQM-UHFFFAOYSA-N 2-bromo-6-fluoroaniline Chemical compound NC1=C(F)C=CC=C1Br ALZFPYUPNVLVQM-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- FWYSMLBETOMXAG-QHCPKHFHSA-N letermovir Chemical compound COC1=CC=CC(N2CCN(CC2)C=2N([C@@H](CC(O)=O)C3=CC=CC(F)=C3N=2)C=2C(=CC=C(C=2)C(F)(F)F)OC)=C1 FWYSMLBETOMXAG-QHCPKHFHSA-N 0.000 description 2
- 229950010668 letermovir Drugs 0.000 description 2
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 2
- 229910000105 potassium hydride Inorganic materials 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 241000701022 Cytomegalovirus Species 0.000 description 1
- 206010011831 Cytomegalovirus infection Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 230000000735 allogeneic effect Effects 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000011134 hematopoietic stem cell transplantation Methods 0.000 description 1
- 231100000171 higher toxicity Toxicity 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
- C07D239/80—Oxygen atoms
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a preparation method of a rituximab intermediate, which comprises the following steps: reacting o-fluoroaniline with paraformaldehyde and hydrogen chloride gas in an acid solvent to obtain a compound I; adding the compound I into an alcohol solvent, and adding urotropine for reaction to obtain a compound II; adding the compound II into toluene solvent, and then adding phenyl chloroformate to react to obtain a compound III; reacting the compound III with trimethyl phosphate in tetrahydrofuran solution to obtain a compound IV; reacting the compound IV with 2-methoxy-5-trifluoromethyl aniline under the action of a catalyst to obtain a compound V; adding a solvent and an organic base into the compound V, and reacting the compound V to obtain the compound TM. The invention takes o-fluoroaniline as a raw material, and obtains a target product, namely the Laitemivir intermediate TM through reaction. The adopted raw materials are low in price, the use of triphosgene with high toxicity is avoided, the safety is good, the large-scale production is facilitated, and the cost is low.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a preparation method of a rituximab intermediate.
Background
Letermovir (Letermovir) was marketed in the United states at 11 months 2017, and is primarily used to treat adult patients who were positive for cytomegalovirus serum following allogeneic hematopoietic stem cell transplantation, and to prevent CMV infection.
Wherein, the preparation route commonly adopted for preparing the Latermopevir intermediate methyl 2- (8-fluoro-3- (2-methoxy-5- (trifluoromethyl) phenyl) -2-oxo-1, 2,3, 4-tetrahydroquinazolin-4-yl) acetate (TM) is as follows:
route one:
the problems with this route are: 1) The third step of palladium catalyst is about 3% of the weight of the substrate, and the cost is high;
2) The raw material 2-bromo-6-fluoroaniline has higher price and is not easy to obtain; 3) The third step of reaction uses acetic acid as solvent, and the fuming sulfuric acid is used in a large amount, and the weight ratio of fuming sulfuric acid to the substrate is 1:1.
Route two:
the problems with this route are: 1) The dosage of the palladium catalyst in the third step is about 13.2 percent of the weight of the substrate, and the cost is high; 2) Triphosgene is used in the first step, and has extremely toxicity; 3) In the third step, acetic acid is used as a solvent, and fuming sulfuric acid is used.
Therefore, the prior art routes for preparing the intermediate methyl (TM) of rituximab 2- (8-fluoro-3- (2-methoxy-5- (trifluoromethyl) phenyl) -2-oxo-1, 2,3, 4-tetrahydroquinazolin-4-yl) acetate mostly employ expensive raw materials, such as: palladium catalyst (20 ten thousand/kg), 2-bromo-6-fluoroaniline and triphosgene with greater toxicity. Is not beneficial to the large-scale production and has higher cost.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides a preparation method of a rituximab intermediate.
The preparation method of the rituximab intermediate provided by the invention adopts the following technical scheme:
a method for preparing a rituximab intermediate, comprising the following steps:
the method comprises the following steps: carrying out chloromethylation reaction on o-fluoroaniline, paraformaldehyde and hydrogen chloride gas in an acid solvent to obtain a compound I;
the following reactions: adding the compound I obtained through the step into an alcohol solvent, and then adding urotropine to perform a somal reaction to obtain a compound II;
the following steps: adding the compound II into a toluene solvent, and then adding alkali and phenyl chloroformate to carry out aminoacylation reaction to obtain a compound III;
fourth, the Horn-Wartz-Eymond reaction: carrying out a Hohnal-Wolfraw-Emmens reaction on the compound III and trimethyl phosphate acetate in tetrahydrofuran solution to obtain a compound IV;
fifthly, aminolysis reaction: carrying out aminolysis reaction on the compound IV and 2-methoxy-5-trifluoromethyl aniline under the action of a catalyst to obtain a compound V;
sixth, cyclization reaction: adding a solvent and an organic base into the compound V, and carrying out an organic base catalyzed cyclization reaction on the compound V to obtain the rituximab intermediate.
Preferably, the acidic solvent in the step (A) is acetic acid or trifluoroacetic acid, the reaction temperature is 60-70 ℃, the time for introducing hydrogen chloride gas is 2-4 h, and the mass ratio of o-fluoroaniline to acidic solvent to paraformaldehyde is 1:2.65-3.0:2.03-3.0.
Wherein, the consumption of hydrogen chloride gas is based on the reaction monitoring, and when the consumption of paraformaldehyde is less than 1.1 times of the consumption of o-fluoroaniline, the o-fluoroaniline is incomplete in reaction and difficult to purify.
Preferably, in the step (II), the mass ratio of the compound I to urotropine is 1:0.18-0.3, the reaction temperature is 25-30 ℃, and the reaction time is 2-4 h.
Preferably, the reaction temperature in the step three is 25-30 ℃, the reaction time is 15-20 h, the alkali is one of sodium bicarbonate and potassium bicarbonate, and the compound II: alkali: the mass ratio of the phenyl chloroformate is 1:1.2-1.6: 1.38 to 1.5.
Wherein, when the consumption of alkali is lower, the reaction is incomplete, the yield is low, and the purification difficulty is increased.
Preferably, the reaction temperature in the step is 25-30 ℃, the reaction time is 15-20 h, and the mass ratio of the compound III to the trimethyl phosphate acetate is 1:0.64-0.9.
Wherein, when the amount of trimethyl phosphate is more than 1 time the amount of compound III, side reactions are increased and economical efficiency is lowered.
Preferably, the reaction time in the step is 6-10 h, the reaction temperature is 25-30 ℃, the catalyst is one of 4-dimethylaminopyridine and imidazole, and the mass ratio of the compound IV to 2-methoxy-5-trifluoromethylaniline is 1:0.63-0.8.
Preferably, the reaction time in the step (II) is 6-7 h, the reaction temperature is 25-30 ℃, the solvent is n-butyronitrile, the organic base is one of diisopropylamine and 4-dimethylaminopyridine, and the mass ratio of the compound V to the organic base is 1:0.28-0.4.
In summary, the invention has the following beneficial technical effects:
according to the invention, o-fluoroaniline is used as a raw material, and target Lattmopevir intermediate TM is obtained through chloromethylation reaction, somley reaction, aminoacylation reaction, holland-Voltz-Eymond reaction, aminolysis and cyclization: methyl 2- (8-fluoro-3- (2-methoxy-5- (trifluoromethyl) phenyl) -2-oxo-1, 2,3, 4-tetrahydroquinazolin-4-yl) acetate. The adopted raw materials are low in price, the use of triphosgene with high toxicity is avoided, the safety is good, the large-scale production is facilitated, and the cost is low.
Detailed Description
The present invention will be described in further detail below.
The embodiment of the invention discloses a preparation method of a rituximab intermediate.
The reaction equation for preparing the rituximab intermediate is as follows:
example 1
A. Preparation of Compound I
2.22Kg of o-fluoroaniline and 5.90Kg of acetic acid are added into a 10L reaction bottle, 4.5Kg of paraformaldehyde is slowly added, and the mixture is heated to 65 ℃ in a water bath, so that tail gas absorption is finished. And introducing dry hydrogen chloride gas for 3h. The high performance liquid phase monitors that the o-fluoroaniline is completely converted. After recovering acetic acid by concentrating under reduced pressure, ethyl acetate is added for crystallization to obtain an off-white solid. The solid obtained was added to 5L of 5% aqueous sodium bicarbonate solution, the separated solution was extracted with 10L of ethyl acetate, and the organic phase was concentrated by drying to obtain 2.39kg of Compound I as a pale brown oil, yield 75% and 98.5% by HPLC.
B. Preparation of Compound II
2.2Kg of Compound I was put into a 10L reaction flask containing 6Kg of 80% ethanol solvent, 400g of urotropine was further added, and the mixture was reacted at 25℃for 3 hours, and the temperature was slowly raised to reflux, and the reflux was continued for 4 hours. The high performance liquid phase monitors that the compound I is completely converted, ethanol is distilled off and cooled to 20 ℃, ethyl acetate is added for extraction and separation, the organic phase is dried by anhydrous sodium sulfate, and then 1.63kg of oily compound II is obtained by concentrating and recovering ethyl acetate, and the yield is 85% and the HPLC is 99.2%.
C. Preparation of Compound III
1.6Kg of Compound II, 5Kg of toluene, 2Kg of water and 1.92Kg of sodium hydrogencarbonate were charged into a 10L reaction flask, and 2.2Kg of phenyl chloroformate was further added thereto and stirred at 25℃for 15 hours. After the conversion of the raw materials is detected by sampling, the raw materials are filtered and washed to obtain white solid, and about 2.83kg of white solid compound III is obtained by baking the raw materials, wherein the yield is 95% and the HPLC is 99%.
D. Preparation of Compound IV
500g of sodium hydride (60%) is weighed and slowly added into 2kg of tetrahydrofuran solution, the temperature is reduced to-5 ℃, and 1.79kg of trimethyl phosphate acetate is added dropwise at-5 ℃. After the dripping is finished, the reaction is carried out for 0.5h under the heat preservation. 2.8kg of a solution of Compound III in 5kg of tetrahydrofuran are added dropwise at a temperature of 5 ℃. After the completion of the dropwise addition, the reaction was carried out at 25℃for 15 hours. Cooling to 0 ℃, and dripping 1.5kg of water. Separating, adding 6kg of ethyl acetate into the water phase, and extracting. The organic phases were combined, washed with water and dried over anhydrous sodium sulfate. After concentrating about 70% ethyl acetate under reduced pressure, cooling to 3 ℃ and crystallizing and purifying to obtain 2.38kg of white solid compound IV, the yield is 70%, and the HPLC is 99.1%.
E. Preparation of Compound V
2.3kg of Compound IV was weighed, 6.5kg of toluene, 100g of 4-dimethylaminopyridine and 1.45kg of 2-methoxy-5-trifluoromethylaniline were added, the system was heated to reflux, and the reflux was carried out at 25℃for 8 hours, after which TLC detection was carried out, after complete conversion of Compound IV, filtration and washing with toluene gave Compound V as a white solid, 2.86kg, yield 95% and HPLC:99.2%.
F. Preparation of TM
2.82kg of compound V is weighed, 15kg of n-butyronitrile and 790g of diisopropylamine are added, the temperature is raised, the solution is heated and refluxed, after clarification, solids are gradually separated out, the solution is refluxed at 25 ℃ for 6 hours, then sampling detection is carried out, and after the conversion of the compound V is completed, the temperature is reduced to-5 ℃. Filtration and washing of n-butyronitrile gave 2.7kg of white solid TM in 96% yield, 99.85% by HPLC.
Example 2
A. Preparation of Compound I
2.22Kg of o-fluoroaniline and 6.66Kg of trifluoroacetic acid are added into a 10L reaction bottle, 6.66Kg of paraformaldehyde is slowly added, and the mixture is heated to 70 ℃ in a water bath, so that tail gas absorption is finished. And introducing dry hydrogen chloride gas for 2h. The high performance liquid phase monitors that the o-fluoroaniline is completely converted. After recovering trifluoroacetic acid by concentrating under reduced pressure, ethyl acetate is added for crystallization to obtain an off-white solid. The solid obtained was added to 6L of 5% aqueous sodium bicarbonate solution, the separated solution was extracted with 10L of ethyl acetate, and the organic phase was concentrated by drying to obtain 2.70kg of Compound I as a pale brown oil, yield 85% and HPLC 98.8%.
B. Preparation of Compound II
2.2Kg of Compound I was added to a 10L reaction flask containing 6Kg of 80% ethanol solvent, 660g of urotropine was further added, and the mixture was reacted at 30℃for 2 hours, and the temperature was slowly raised to reflux, and the reflux was continued for 5 hours. The high performance liquid phase monitors that the compound I is completely converted, ethanol is distilled off and cooled to 25 ℃, ethyl acetate is added for extraction and separation, the organic phase is dried by anhydrous sodium sulfate, and then ethyl acetate is concentrated and recovered to obtain 1.57kg of oily compound II, the yield is 82%, and the HPLC is 99.3%.
C. Preparation of Compound III
1.6Kg of Compound II, 5Kg of toluene, 2Kg of water and 2.56Kg of sodium hydrogencarbonate were charged into a 10L reaction flask, and 2.4Kg of phenyl chloroformate was further added thereto and stirred at 30℃for 20 hours. After the conversion of the raw materials is detected by sampling, the raw materials are filtered and washed to obtain white solid, and about 2.88kg of white solid compound III is obtained by baking the raw materials, wherein the yield is 96 percent and the HPLC is 99.2 percent.
D. Preparation of Compound IV
850g of potassium hydride (35%) are weighed and slowly added into 2kg of tetrahydrofuran solution, the temperature is reduced to 5 ℃, and 2.52kg of trimethyl phosphate acetate is added dropwise at the temperature of 5 ℃. After the dripping is finished, the reaction is carried out for 0.5h under the heat preservation. 2.8kg of a solution of Compound III in 5kg of tetrahydrofuran are added dropwise at-5 ℃. After the completion of the dropwise addition, the reaction was carried out at 30℃for 20 hours. Cooling to 5 ℃, and dripping 1.5kg of water. Separating, adding 6kg of ethyl acetate into the water phase, and extracting. The organic phases were combined, washed with water and dried over anhydrous sodium sulfate. After concentrating about 70% ethyl acetate under reduced pressure, cooling to 10 ℃ and crystallizing and purifying to obtain 2.55kg of white solid compound IV, the yield is 75%, and the HPLC is 99.2%.
E. Preparation of Compound V
2.3kg of Compound IV is weighed, 6.5kg of toluene, 50g of imidazole and 1.84kg of 2-methoxy-5-trifluoromethylaniline are added, the system is heated to reflux, the reflux is carried out for 8 hours at 30 ℃, after that, TLC detection is carried out, after complete conversion of Compound IV, filtration and washing with toluene are carried out, 2.89kg of white solid compound V is obtained, the yield is 96%, and HPLC is 99.4%.
F. Preparation of TM
2.82kg of compound V is weighed, 15kg of n-butyronitrile and 1.13kg of 4-dimethylaminopyridine are added, the temperature is raised, the solution is heated and refluxed, after the solution is clarified, solids are gradually separated out, the solution is refluxed at 30 ℃ for 7 hours, then sampling detection is carried out, and after the conversion of the compound V is completed, the temperature is reduced to 5 ℃. Filtration and washing of n-butyronitrile gave 2.67kg of white solid TM in 95% yield, 99.80% by HPLC.
Example 3
A. Preparation of Compound I
2.22Kg of o-fluoroaniline and 6.22Kg of trifluoroacetic acid are added into a 10L reaction bottle, 6.22Kg of paraformaldehyde is slowly added, and the mixture is heated to 60 ℃ in a water bath, so that tail gas absorption is finished. And introducing dry hydrogen chloride gas for 2h. The high performance liquid phase monitors that the o-fluoroaniline is completely converted. After recovering trifluoroacetic acid by concentrating under reduced pressure, ethyl acetate is added for crystallization to obtain an off-white solid. The solid obtained was added to 6L of 5% aqueous sodium bicarbonate solution, the separated solution was extracted with 10L of ethyl acetate, and the organic phase was concentrated by drying to obtain 2.70kg of Compound I as a pale brown oil, yield 85% and HPLC 98.8%.
B. Preparation of Compound II
2.2Kg of Compound I was added to a 10L reaction flask containing 6Kg of 80% ethanol solvent, and 506g of urotropine was further added thereto, and the mixture was reacted at 27℃for 2 hours, and the temperature was slowly raised to reflux, and the reflux was continued for 5 hours. The high performance liquid phase monitors that the compound I is completely converted, ethanol is distilled off and cooled to 25 ℃, ethyl acetate is added for extraction and separation, the organic phase is dried by anhydrous sodium sulfate, and then ethyl acetate is concentrated and recovered to obtain 1.57kg of oily compound II, the yield is 82%, and the HPLC is 99.3%.
C. Preparation of Compound III
1.6Kg of Compound II, 5Kg of toluene, 2Kg of water and 2.24Kg of sodium hydrogencarbonate were charged into a 10L reaction flask, and 2.29Kg of phenyl chloroformate was further added thereto and stirred at 28℃for 17 hours. After the conversion of the raw materials is detected by sampling, the raw materials are filtered and washed to obtain white solid, and about 2.88kg of white solid compound III is obtained by baking the raw materials, wherein the yield is 96 percent and the HPLC is 99.2 percent.
D. Preparation of Compound IV
850g of potassium hydride (35%) are weighed and slowly added into 2kg of tetrahydrofuran solution, the temperature is reduced to 5 ℃, and 2.1kg of trimethyl phosphate acetate is added dropwise at the temperature of 5 ℃. After the dripping is finished, the reaction is carried out for 0.5h under the heat preservation. 2.8kg of a solution of Compound III in 5kg of tetrahydrofuran are added dropwise at-5 ℃. After the completion of the dropwise addition, the reaction was carried out at 27℃for 18 hours. Cooling to 5 ℃, and dripping 1.5kg of water. Separating, adding 6kg of ethyl acetate into the water phase, and extracting. The organic phases were combined, washed with water and dried over anhydrous sodium sulfate. After concentrating about 70% ethyl acetate under reduced pressure, cooling to 10 ℃ and crystallizing and purifying to obtain 2.55kg of white solid compound IV, the yield is 75%, and the HPLC is 99.2%.
E. Preparation of Compound V
2.3kg of Compound IV is weighed, 6.5kg of toluene, 50g of imidazole and 1.61kg of 2-methoxy-5-trifluoromethylaniline are added, the system is heated to reflux, the reflux is carried out for 6 hours at 28 ℃, after that, TLC detection is carried out, after complete conversion of Compound IV, filtration and washing with toluene are carried out, 2.89kg of white solid compound V is obtained, the yield is 96%, and HPLC is 99.4%.
F. Preparation of TM
2.82kg of compound V is weighed, 15kg of n-butyronitrile and 0.96kg of 4-dimethylaminopyridine are added, the temperature is raised, the solution is heated and refluxed, after the solution is clarified, solids are gradually separated out, the solution is refluxed at 30 ℃ for 6 hours, then sampling detection is carried out, and after the conversion of the compound V is completed, the temperature is reduced to 5 ℃. Filtration and washing of n-butyronitrile gave 2.67kg of white solid TM in 95% yield, 99.80% by HPLC.
From examples 1 to 3, the invention adopts o-fluoroaniline as a raw material, and obtains a compound I through chloromethylation reaction, obtains a compound II through Somley reaction, obtains a compound III through aminoacylation reaction, obtains a compound IV through Holland-Wolz-Emmerst reaction, obtains a compound V through aminolysis reaction and obtains a target compound Lytermopevir intermediate TM through cyclization reaction: methyl 2- (8-fluoro-3- (2-methoxy-5- (trifluoromethyl) phenyl) -2-oxo-1, 2,3, 4-tetrahydroquinazolin-4-yl) acetate. The adopted raw materials have lower price, higher yield and purity, and the use of triphosgene with higher toxicity is avoided, the safety is better, the large-scale production is facilitated, and the cost is low.
The above embodiments are not intended to limit the scope of the present invention, so: all equivalent changes in structure, shape and principle of the invention should be covered in the scope of protection of the invention.
Claims (5)
1. A preparation method of a rituximab intermediate is characterized by comprising the following steps: the method comprises the following steps:
the method comprises the following steps: carrying out chloromethylation reaction on o-fluoroaniline, paraformaldehyde and hydrogen chloride gas in an acid solvent to obtain a compound I; wherein the reaction temperature is 60-70 ℃, the time for introducing the hydrogen chloride gas is 2-4 hours, and the mass ratio of the o-fluoroaniline to the acidic solvent to the paraformaldehyde is 1:2.65-3.0:2.03-3.0;
the following reactions: adding the compound I obtained through the step into an alcohol solvent, and then adding urotropine to perform a somal reaction to obtain a compound II; wherein the reaction temperature is 25-30 ℃, the reaction time is 2-4 h, and the mass ratio of the compound I to urotropine is 1:0.18-0.3;
the following steps: adding the compound II into a toluene solvent, and then adding alkali and phenyl chloroformate to carry out aminoacylation reaction to obtain a compound III; wherein the reaction temperature is 25-30 ℃, the reaction time is 15-20 h, and the compound II: alkali: the mass ratio of the phenyl chloroformate is 1:1.2-1.6: 1.38 to 1.5;
fourth, the Horn-Wartz-Eymond reaction: carrying out a Hohnal-Wolfraw-Eymus reaction on the compound III and trimethyl phosphate acetate in tetrahydrofuran solution to obtain a compound IV; wherein the reaction temperature is 25-30 ℃, the reaction time is 15-20 h, and the mass ratio of the compound III to the trimethyl phosphate acetate is 1:0.64 to 0.9;
fifthly, aminolysis reaction: carrying out aminolysis reaction on the compound IV and 2-methoxy-5-trifluoromethyl aniline under the action of a catalyst to obtain a compound V; wherein the reaction time is 6-10 h, the reaction temperature is 25-30 ℃, and the mass ratio of the compound IV to the 2-methoxy-5-trifluoromethylaniline is 1:0.63-0.8;
sixth, cyclization reaction: adding a solvent and organic base into a compound V, and carrying out an organic base catalyzed cyclization reaction on the compound V to obtain a rituximab intermediate; wherein the reaction temperature is 25-30 ℃, the reaction time is 6-7 h, and the mass ratio of the compound V to the organic base is 1:0.28-0.4.
2. The method for preparing the letromycin intermediate as claimed in claim 1, wherein: in the step, the acidic solvent is acetic acid or trifluoroacetic acid.
3. The method for preparing the letromycin intermediate as claimed in claim 1, wherein: in the step III, the alkali is one of sodium bicarbonate and potassium bicarbonate.
4. The method for preparing the letromycin intermediate as claimed in claim 1, wherein: in the step II, the catalyst is one of 4-dimethylaminopyridine or imidazole.
5. The method for preparing the letromycin intermediate as claimed in claim 1, wherein: in the step (II), the solvent is n-butyronitrile, and the organic base is one of diisopropylamine or 4-dimethylaminopyridine.
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