CN111747941B - Synthesis method of leflunomide - Google Patents
Synthesis method of leflunomide Download PDFInfo
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- CN111747941B CN111747941B CN201910251924.1A CN201910251924A CN111747941B CN 111747941 B CN111747941 B CN 111747941B CN 201910251924 A CN201910251924 A CN 201910251924A CN 111747941 B CN111747941 B CN 111747941B
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- 238000001308 synthesis method Methods 0.000 title claims abstract description 14
- VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 title claims abstract description 11
- 229960000681 leflunomide Drugs 0.000 title claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 95
- 230000002829 reductive effect Effects 0.000 claims abstract description 47
- 238000000034 method Methods 0.000 claims abstract description 24
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 20
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 18
- 230000008569 process Effects 0.000 claims abstract description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 74
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 48
- 150000001875 compounds Chemical class 0.000 claims description 47
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 44
- 238000003756 stirring Methods 0.000 claims description 42
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 37
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 35
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 33
- 239000012043 crude product Substances 0.000 claims description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- 239000012074 organic phase Substances 0.000 claims description 22
- 239000007788 liquid Substances 0.000 claims description 20
- 239000007787 solid Substances 0.000 claims description 20
- 239000000047 product Substances 0.000 claims description 19
- 238000001914 filtration Methods 0.000 claims description 18
- 230000001105 regulatory effect Effects 0.000 claims description 18
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 17
- 238000001035 drying Methods 0.000 claims description 15
- 239000012065 filter cake Substances 0.000 claims description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 14
- 239000000243 solution Substances 0.000 claims description 13
- 239000005457 ice water Substances 0.000 claims description 12
- 229940126062 Compound A Drugs 0.000 claims description 11
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 11
- 239000007821 HATU Substances 0.000 claims description 10
- 230000001276 controlling effect Effects 0.000 claims description 9
- 238000002425 crystallisation Methods 0.000 claims description 9
- 230000008025 crystallization Effects 0.000 claims description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 7
- 239000008346 aqueous phase Substances 0.000 claims description 7
- 239000012295 chemical reaction liquid Substances 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 7
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- 239000012528 membrane Substances 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 abstract description 12
- 239000002904 solvent Substances 0.000 abstract description 11
- 229910052763 palladium Inorganic materials 0.000 abstract description 6
- 239000003054 catalyst Substances 0.000 abstract description 5
- 229910001385 heavy metal Inorganic materials 0.000 abstract description 5
- 230000006340 racemization Effects 0.000 abstract description 5
- 125000004432 carbon atom Chemical group C* 0.000 abstract description 3
- 238000010511 deprotection reaction Methods 0.000 abstract description 3
- 230000002349 favourable effect Effects 0.000 abstract description 3
- 125000000524 functional group Chemical group 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000007086 side reaction Methods 0.000 abstract description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 12
- 239000002994 raw material Substances 0.000 description 11
- 239000000126 substance Substances 0.000 description 11
- 230000002194 synthesizing effect Effects 0.000 description 11
- 239000002253 acid Substances 0.000 description 10
- 108010064548 Lymphocyte Function-Associated Antigen-1 Proteins 0.000 description 7
- 208000003556 Dry Eye Syndromes Diseases 0.000 description 6
- 230000006837 decompression Effects 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 230000035484 reaction time Effects 0.000 description 6
- 102000015271 Intercellular Adhesion Molecule-1 Human genes 0.000 description 5
- 108010064593 Intercellular Adhesion Molecule-1 Proteins 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 229910019142 PO4 Inorganic materials 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 4
- 239000010452 phosphate Substances 0.000 description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical group [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
- 206010013774 Dry eye Diseases 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 2
- 210000001744 T-lymphocyte Anatomy 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- JFOZKMSJYSPYLN-QHCPKHFHSA-N lifitegrast Chemical compound CS(=O)(=O)C1=CC=CC(C[C@H](NC(=O)C=2C(=C3CCN(CC3=CC=2Cl)C(=O)C=2C=C3OC=CC3=CC=2)Cl)C(O)=O)=C1 JFOZKMSJYSPYLN-QHCPKHFHSA-N 0.000 description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 description 2
- 235000011009 potassium phosphates Nutrition 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- XHRPRBRZRJWLMD-UHFFFAOYSA-M 5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxylate Chemical group ClC1=C2CCNCC2=CC(=C1C(=O)[O-])Cl XHRPRBRZRJWLMD-UHFFFAOYSA-M 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 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
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 238000000119 electrospray ionisation mass spectrum Methods 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 210000001339 epidermal cell Anatomy 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000003960 inflammatory cascade Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229960005381 lifitegrast Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 208000005494 xerophthalmia Diseases 0.000 description 1
- 229940023106 xiidra Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a synthesis method of leflunomide. The Li Feisi special synthesis method has short synthesis route, compared with the prior art, reaction steps such as protection and deprotection on functional groups are reduced, chiral structures are introduced only in the last step, the configuration is kept unchanged in the reaction, and racemization risk of chiral carbon atoms in the reaction process is reduced; the reaction condition is mild, the solvent type and side reaction are less, and heavy metals such as palladium are not used as catalysts in the synthesis process, so that the method is environment-friendly and the cost is reduced; meanwhile, the total yield of the whole reaction route is high, and the method is favorable for large-scale industrial production.
Description
Technical Field
The invention relates to a synthesis method of leflunomide, in particular to a chemical synthesis method of a leflunomide bulk drug (Lifiteglast), belonging to the technical field of chemical synthesis processes.
Background
With the vigorous development of the communication industry, the mobile phone party and the low head group which are visible everywhere nowadays are induced, and the daily eye strength is improved. The existing investigation data show that with age, the risk of dry eye disease increases gradually: the prevalence rate of people aged 30-40 is more than 20%; the prevalence of people over 70 years old is as high as 36.1%; whereas the incidence rate for male patients is 14.9%; female patients have a prevalence of 22.8%. In addition, with the popularization of devices such as mobile phones and computers, the incidence of dry eye disease in young people has increased year by year, so that ophthalmic diseases represented by dry eye disease have increasingly become popular. Worldwide, the incidence of xerophthalmia is about 5% -34% of the general population, and the incidence is higher in regions where the living standard is higher, the electronic products are more popular and the use rate of the electronic products is higher.
Lymphocyte function-associated antigen 1 (LFA-1) is a cell surface adhesion protein, and its cognate ligand intercellular adhesion molecule-1 (ICAM-1) is expressed on the surface of epidermal and endothelial cells after inflammation. LFA-1, upon binding to ICAM-1, can trigger homing and activation of ocular surface T cells and subsequent cytokine release, leading to localized inflammation. This mechanism plays a role in the inflammatory cascade of dry eye, and thus LFA-1/ICAM-1 interaction inhibitors reduce ocular surface T-cell mediated inflammatory levels by inhibiting the binding of both.
Lifeprist (Lifitegrast), developed by Shire, UK, was the first small molecule LFA-1/ICAM-1 interaction antagonist marketed in bulk worldwide and was FDA approved for the treatment of dry eye signs and symptoms in 2016, 7, under the trade name Xiidra. This is the first FDA approved new lymphocyte function-associated antigen 1 (LFA-1) antagonist for the treatment of dry eye, having the chemical structural formula:
currently, there are three main routes to the published synthetic patent WO2014018748A1 of Li Feisi, as follows:
route one:
the protective groups of amino and carboxyl are introduced in the reaction process of the first route, so that the production period is prolonged, the production cost is increased, and the green chemical requirements are not met; meanwhile, palladium is used as a catalyst to crack benzyl, so that racemization probability of a chiral center is increased, and an ee% value becomes a key point to be controlled in the reaction process; and heavy metals such as palladium are introduced in the reaction process, so that the harm to human bodies and the environment is caused.
Route two:
compared with the first route, the second route not only introduces chiral structures from the starting materials, but also causes racemization of chiral centers in the subsequent reaction steps, so that the ee% value is also the key point to be controlled in the reaction process; meanwhile, the method also has the protection groups of amino and carboxyl introduced in the reaction process, so that the production period is prolonged, the production cost is increased, and the method does not meet the green chemical requirements; the adoption of heavy metals such as palladium and the like causes harm to human bodies and the environment.
Route three:
compared with the first and second routes, the third route has more reaction steps, has all the defects of the first and second routes, and has reversible reaction in the upper methylsulfonyl step, thus being not easy to purify, leading to lower yield and greatly increasing production cost.
In conclusion, the preparation Li Feisi in the prior art has the problems of complex reaction process, difficult purification of products, low yield, long production period, high cost, large harm to human bodies and environment and the like. Therefore, a need exists for a synthesis method of Li Feisi which is simple and convenient to prepare, low in cost, environment-friendly and high in yield.
Disclosure of Invention
In order to solve the problems, the invention provides a synthesis method of leflunomide, which comprises the following steps:
step 1: stirring the compound A and the compound B in a solvent uniformly, adding DIPEA for reaction, and purifying a reaction solution obtained by the reaction to obtain a compound C;
step 2: stirring the compound C and HATU in a solvent uniformly, adding DIPEA, and reacting to obtain an intermediate state after the reaction is finished;
step 3: dissolving a compound D and soluble phosphate in pure water to obtain a standby liquid; and adding the standby liquid into an intermediate state for reaction, and purifying the reaction liquid obtained by the reaction to obtain the catalyst.
Further, in the step 1, the molar ratio of the compound A to the compound B, DIPEA is 1:0.6-1.5:2-6; the weight-volume ratio of the compound A to the solvent is 1:5-15 (w/v); and/or in the step 2 and the step 3, the molar ratio of the compound C to the compound D, HATU, DIPEA to the soluble phosphate is 1:1-2:1-4:2-5; the weight-volume ratio of the compound C to the solvent is 1:5-20 (w/v); the weight-volume ratio of the compound D to the pure water is 1:5-15 (w/v).
Further, in the step 1, the molar ratio of the compound A to the compound B, DIPEA is 1:1:4; the weight-volume ratio of the compound A to the solvent is 1:10; and/or in step 2 and step 3, the molar ratio of compound C, compound D, HATU, DIPEA, soluble phosphate is 1:1.5:1:1.5:3; the weight-volume ratio of the compound C to the solvent is 1:10 (w/v); the weight-to-volume ratio of the compound D to pure water was 1:10 (w/v).
Further, in the step 1, the solvent is tetrahydrofuran; and/or, in the step 2, the solvent is tetrahydrofuran; and/or, in step 3, the soluble phosphate is potassium phosphate or sodium phosphate, preferably potassium phosphate.
Further, in the step 1, the DIPEA is added slowly and dropwise; the temperature of the whole process of the step 1 is 0-10 ℃; the reaction time is 1-3 h; the purification is that after the pH value is regulated to 1-4 by strong acid, the temperature is reduced, crystallization is carried out, filtration is carried out, filter cakes are washed, and decompression drying is carried out; wherein the strong acid is sulfuric acid or hydrochloric acid.
Further, in step 1, the temperature of the whole process of step 1 is 5 ℃; the reaction time is 2h; the purification is that strong acid adjusts the pH value to 3, the temperature is reduced to 0-10 ℃ for crystallization, the filtration is carried out, the filter cake is washed once by purified water and tetrahydrofuran respectively, and the filter cake is dried for 1-3 hours under reduced pressure at 50-60 ℃; wherein the strong acid is hydrochloric acid.
Further, in the step 2, the DIPEA is added slowly and dropwise; the temperature of stirring and adding DIPEA is 0-10 ℃, and the temperature of reaction after dripping is 20-30 ℃; the reaction time is 15-30 h.
Further, in the step 2, the temperature of stirring and dripping DIPEA is 5 ℃, and the temperature of reaction after dripping is 25 ℃; the reaction time was 20h.
Further, in step 3, the adding of the standby liquid into the intermediate state is slow dropping of the standby liquid into the intermediate state; the temperature of the liquid to be used is 0-10 ℃, and the temperature of the reaction after the dripping is 20-30 ℃; the reaction time is 15-30 h; the purification is that after the pH value is regulated to 2-4 by strong acid, separating liquid, extracting, merging organic phases, washing and concentrating under reduced pressure to dryness to obtain a crude product in a lower aqueous phase, directly concentrating the upper organic phase under reduced pressure to dryness to obtain a crude product, dissolving the merged crude product, filtering, regulating the pH value to 2-4 by strong acid, stirring and crystallizing for 1-4 hours, filtering to obtain a solid, and drying under reduced pressure to constant weight; wherein the strong acid is hydrochloric acid and sulfuric acid; the extraction is carried out by mixing ethyl acetate and tetrahydrofuran, and the volume ratio of the ethyl acetate to the tetrahydrofuran is 1:1-2.
Further, in the step 3, the temperature of the dropwise adding standby liquid is 5 ℃, and the temperature of the reaction after the dropwise adding is 25 ℃; the reaction time is 20h; the purification is that after the pH value is regulated to 3 by strong acid, liquid separation is carried out, the lower water phase is extracted, the organic phase and saturated saline water are combined, washed and concentrated to dryness under reduced pressure to obtain a crude product, the upper organic phase is directly concentrated to dryness under reduced pressure to obtain a crude product, the crude product after the combination is dissolved, filtered, the pH value is regulated to 3 by strong acid, stirred and crystallized for 2 hours, and the solid is obtained after the filtration, dried to constant weight under reduced pressure at 50-60 ℃; wherein the strong acid is hydrochloric acid; the extraction is carried out by mixing ethyl acetate and tetrahydrofuran, and the volume ratio of the ethyl acetate to the tetrahydrofuran is 1:1.
In the invention, w/v represents the mass-volume ratio, and the unit is g/ml.
The Li Feisi special synthesis method has short synthesis route, compared with the prior art, reaction steps such as protection and deprotection on functional groups are reduced, chiral structures are introduced only in the last step, the configuration is kept unchanged in the reaction, and racemization risk of chiral carbon atoms in the reaction process is reduced; the reaction condition is mild, the solvent type and side reaction are less, and heavy metals such as palladium are not used as catalysts in the synthesis process, so that the method is environment-friendly and the cost is reduced; meanwhile, the total yield of the whole reaction route is high, and the method is favorable for large-scale industrial production.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Drawings
FIG. 1 shows the product obtained in example 2 1 HNMR profile.
FIG. 2 is an ESI-MS spectrum of the product obtained in example 2.
FIG. 3 is a diagram of leflunomide 1 HNMR literature profile.
FIG. 4 is an ESI-MS literature pattern of leflunomide.
Detailed Description
1. The chemical names and sources of the main raw materials and the dissolving agents used in the specific embodiment of the invention are as follows:
compound a: the chemical name is 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline-6-carboxylate, which is provided by the company of the pharmaceutical industry, inc.
Compound B: the chemical name is benzofuran-6-formyl chloride, which is provided by Chengdu Pont pharmaceutical Co.
Compound C: the chemical name is (2- (benzofuran-6-formyl) -5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline-6-carboxylic acid).
Compound D: the chemical name is (S) -2-amino-3- (3- (methylsulfonyl) phenylpropionic acid) hydrochloride, which is provided by the company of the pharmaceutical industry, inc.
Compound E prepared according to the invention: li Feisi dtex.
HATU: the chemical name is 2- (7-azobenzotriazole) -N, N, N ', N ' -tetramethyl urea hexafluorophosphate, which is produced by Duke's chemical engineering reagent factory.
DIPEA: the chemical name is N, N-diisopropylethylamine, which is produced by Duke Longxiao chemical reagent factory.
THF: the chemical name is tetrahydrofuran, and is produced by Beijing Micida technology Co.
Other materials and equipment used in the embodiments of the present invention are all known products and are obtained by purchasing commercially available products.
2. The special synthetic route for preparing Li Feisi of the invention is as follows:
example 1, method for synthesizing Li Feisi of the invention
(1) Synthesis of Compound C
TABLE 1 Main raw materials and reagents for synthesizing Compound C
The preparation method comprises the following steps:
1) 2.0g of compound A, 1.3g of compound B and 10mLTHF are sequentially added into a 25mL reaction bottle, stirring is started, and ice water bath is cooled to 5+/-2 ℃;
2) After stirring evenly, 1.9g of DIPEA is slowly dripped, the temperature is controlled to be 5+/-2 ℃ in the dripping process, and the temperature is kept to be 5+/-2 ℃ after the dripping is finished for reaction for 2 hours; through HPLC central control reaction, the reaction is finished when the content of the compound B is less than 0.5%;
3) After the reaction, the pH of the reaction solution is regulated to 2 by using 2N hydrochloric acid under stirring, a large amount of solids are precipitated, the temperature is reduced to 0 ℃, stirring crystallization is carried out for 2 hours, a filter cake is obtained by filtering, the filter cake is washed once by using 5mL of pure water, and is washed once by using 5mL of THF, and 2.47g of compound C is obtained by drying under reduced pressure at 50-60 ℃, wherein the purity is 99.4%, and the yield is 89.5%.
(2) Synthesis of Li Feisi t (Compound E) of the present invention
TABLE 2 Main raw materials and reagents for synthesizing Li Feisi dtex (Compound E) of the invention
The preparation method comprises the following steps:
A. 1.5g of compound C, 1.5g of HATU and 7mL of THF are added into a 10mL triangular flask, stirring is started, and ice water bath is cooled to 0-10 ℃;
B. after stirring uniformly, preserving heat, dropwise adding 0.5g of DIPEA at 0-10 ℃, naturally returning to 20-30 ℃ after dropwise adding, reacting for 15+/-2 h, and performing HPLC (high performance liquid chromatography) central control reaction, wherein the intermediate compound is obtained after the reaction is completed when the content of the compound C is less than 0.1%;
C. 1.1g of Compound D, 5.2. 5.2g K are added in a 10mL beaker 3 PO 4 ·7H 2 O and 15mL of pure water are stirred until the solid is completely dissolved, thus obtaining a standby liquid for standby;
D. slowly adding the standby liquid in the C into an intermediate compound by dripping at the temperature of 0-10 ℃, naturally returning to the temperature of 20-30 ℃ for reacting for 15+/-2 hours, and performing a medium-control reaction by HPLC (high performance liquid chromatography), wherein the intermediate compound is less than 0.1% after the reaction is finished, so as to obtain a reaction liquid;
E. post-treatment: adjusting the pH of the reaction solution to 2-3 by using 2N hydrochloric acid, separating, extracting the lower aqueous phase by using 10mL of ethyl acetate/tetrahydrofuran extract (EA: THF=1:1) for 1 time, merging the organic phases, washing the organic phases by using 10mL of saturated saline for 1 time, concentrating under reduced pressure to dryness to obtain a crude product, and directly concentrating the upper organic phase under reduced pressure to dryness to obtain the crude product;
F. purifying a crude product: the crude products are dissolved in NaOH aqueous solution (0.3 g NaOH+30ml pure water) after being combined, the mixture is filtered by a filter membrane, the pH of the filtrate is regulated to 2-4 by 2N hydrochloric acid, the mixture is stirred and crystallized for 2+/-1 h, the product is obtained after filtration, and the mixture is dried to constant weight by a decompression drying oven at 50-60 ℃ to obtain 2.0g of compound E (Li Feisi t), white solid with the purity of 99.7 percent and the yield of 84.7 percent.
Example 2 Synthesis method of Li Feisi Te of the invention
(1) Synthesis of Compound C
TABLE 3 Main raw materials and reagents for synthesizing Compound C
The preparation method comprises the following steps:
1) 15g of compound B, 23.5g of compound A and 150mL of THF are sequentially added into a 500mL reaction bottle, stirring is started, and ice water bath is cooled to 0-10 ℃;
2) After uniformly stirring, slowly dripping 43.0g of DIPEA, controlling the temperature to be 0-10 ℃ in the dripping process, preserving the temperature to be 0-10 ℃ after dripping, reacting for 1-2 h, and controlling the reaction by HPLC (high performance liquid chromatography), wherein the reaction is completed when the content of the compound B is less than 0.5%;
3) After the reaction is finished, the pH of the reaction solution is regulated to 1-3 by 2N hydrochloric acid under stirring, a large amount of solids are separated out, the temperature is reduced to 0-10 ℃, stirring crystallization is carried out for 1-2 hours, a filter cake is obtained by filtering, the filter cake is washed once by 30mL of pure water, and is washed once by 30mL of THF, and 29.2g of compound C is obtained by drying under reduced pressure at 50-60 ℃, wherein the purity is 99.6%, and the yield is 90.1%.
(2) Synthesis of Li Feisi t (Compound E) of the present invention
TABLE 4 Main raw materials and reagents for synthesizing Li Feisi dtex (Compound E) of the invention
A. 15.2g of compound C, 14.8g of HATU and 152mL of THF are added into a 500mL triangular flask, stirring is started, and the temperature is reduced to 0-10 ℃ by ice water bath;
B. after stirring uniformly, preserving heat, dropwise adding 6.1g of DIPEA at 0-10 ℃, naturally returning to 20-30 ℃ after dropwise adding, reacting for 15+/-2 h, and performing HPLC (high performance liquid chromatography) central control reaction, wherein the intermediate compound is obtained after the reaction is completed when the content of the compound C is less than 0.1%;
C. in a 1L beaker was added 19.8g of Compound D, 39.5g K 3 PO 4 ·7H 2 O and 150mL of pure water are stirred until the solid is completely dissolved, thus obtaining a standby liquid for standby;
D. slowly adding the standby liquid in the C into an intermediate compound by dripping at the temperature of 0-10 ℃, naturally returning to the temperature of 20-30 ℃ for reacting for 15+/-2 hours, and performing a medium-control reaction by HPLC (high performance liquid chromatography), wherein the intermediate compound is less than 0.1% after the reaction is finished, so as to obtain a reaction liquid;
E. post-treatment: adjusting the pH of the reaction solution to 2-3 by using 5N hydrochloric acid, separating, extracting the lower aqueous phase by using 60mL ethyl acetate/tetrahydrofuran extract (EA: THF=1:1) for 1 time, merging the organic phases, washing the organic phases by using 60mL saturated saline for 1 time, concentrating under reduced pressure to dryness to obtain a crude product, and directly concentrating the upper organic phase under reduced pressure to dryness to obtain the crude product;
F. purifying a crude product: the crude products are dissolved in NaOH aqueous solution (2.7 g NaOH+300mL pure water) after being combined, the mixture is filtered by a filter membrane, the pH of the filtrate is regulated to 2-4 by 5N hydrochloric acid, the mixture is stirred and crystallized for 2+ -1 h, the product is obtained after filtration, and the mixture is dried to constant weight by a decompression drying oven at 50-60 ℃ to obtain 19g of compound E (Li Feisi t), white solid with the purity of 99.7 percent and the yield of 90.5 percent.
Example 3 Synthesis method of Li Feisi Te of the invention
(1) Synthesis of Compound C
TABLE 5 Main raw materials and reagents for synthesizing Compound C
The preparation method comprises the following steps:
1) Sequentially adding 50g of compound B, 78.23g of compound A and 500mL of THF into a 1000mL reaction bottle, starting stirring, and cooling to 0-10 ℃ in an ice water bath;
2) After uniformly stirring, slowly dripping 143.2g of DIPEA, controlling the temperature to be 0-10 ℃ in the dripping process, preserving the temperature to be 0-10 ℃ after dripping, reacting for 1-2 h, and controlling the reaction by HPLC (high performance liquid chromatography), wherein the reaction is completed when the content of the compound B is less than 0.5%;
3) After the reaction is finished, the pH of the reaction solution is regulated to 1-2 by 2N hydrochloric acid under stirring, a large amount of solids are separated out, the temperature is reduced to 0-10 ℃, stirring crystallization is carried out for 1-2 hours, a filter cake is obtained by filtering, the filter cake is washed once by 100mL of pure water, and is washed once by 100mL of THF, and 98.1g of compound C is obtained by drying under reduced pressure at 50-60 ℃, wherein the purity is 99.5%, and the yield is 90.8%.
(2) Synthesis of Li Feisi t (Compound E) of the present invention
TABLE 6 Main raw materials and reagents for synthesizing Li Feisi dtex (Compound E) of the invention
The preparation method comprises the following steps:
A. 85g of compound C, 82.83g of HATU and 850mL of THF are added into a 3000mL triangular flask, stirring is started, and ice water bath is cooled to 0-10 ℃;
B. after stirring uniformly, keeping the temperature between 0 and 10 ℃ and dropwise adding 42.23 DIPEA, naturally returning to the temperature between 20 and 30 ℃ after the dropwise adding is completed, reacting for 15+/-2 hours, and performing HPLC (high performance liquid chromatography) central control reaction to obtain an intermediate compound after the reaction is completed, wherein the compound C is less than 0.1%;
C. 72.12g of Compound D, 161.83g K are added in a 2000ml beaker 3 PO 4 ·7H 2 O and 850mL of pure water are stirred until the solid is completely dissolved, and a standby liquid is obtained for standby;
D. slowly adding the standby liquid in the C into an intermediate compound by dripping at the temperature of 0-10 ℃, naturally returning to the temperature of 20-30 ℃ for reacting for 15+/-2 hours, and performing a medium-control reaction by HPLC (high performance liquid chromatography), wherein the intermediate compound is less than 0.1% after the reaction is finished, so as to obtain a reaction liquid;
E. post-treatment: adjusting the pH of the reaction solution to 2-3 by using 2N hydrochloric acid, separating, extracting the lower aqueous phase by using 340mL ethyl acetate/tetrahydrofuran extract (EA: THF=1:1) for 1 time, merging organic phases, washing the organic phases by using 340mL saturated saline for 1 time, concentrating under reduced pressure to dryness to obtain a crude product, and directly concentrating the upper organic phase under reduced pressure to dryness to obtain the crude product;
F. purifying a crude product: the crude products are dissolved in NaOH aqueous solution (17.43 g NaOH+1700mL pure water) after being combined, the mixture is filtered by a filter membrane, the pH of the filtrate is regulated to 2-4 by 2N hydrochloric acid, the mixture is stirred and crystallized for 2+ -1 h, the product is obtained after filtration, and the mixture is dried to constant weight by a decompression drying oven at 50-60 ℃ to obtain 111.95g of compound E (Li Feisi T), white solid with purity of 99.5 percent and yield of 83.5 percent.
Example 4 Synthesis method of Li Feisi Te of the invention
(1) Synthesis of Compound C
TABLE 7 Main raw materials and reagents for synthesizing Compound C
The preparation method comprises the following steps:
1) 15g of compound B, 4.7g of compound A and 150mL of THF are sequentially added into a 500mL reaction bottle, stirring is started, and ice water bath is cooled to 0-10 ℃;
2) 2) after uniformly stirring, slowly dripping 21.5g of DIPEA, controlling the temperature to be 0-10 ℃ in the dripping process, and after dripping, keeping the temperature to be 0-10 ℃ for reaction for 1-2 h, wherein the compound B is less than 0.5% through HPLC (high performance liquid chromatography) central control reaction, thus finishing the reaction;
3) After the reaction is finished, the pH of the reaction solution is regulated to 1-2 by 2N hydrochloric acid under stirring, a large amount of solids are separated out, the temperature is reduced to 0-10 ℃, stirring crystallization is carried out for 1-2 hours, a filter cake is obtained by filtering, the filter cake is washed once by 30mL of pure water, and is washed once by 30mL of THF, and the product of 26.4g of the compound C is obtained by drying under reduced pressure at 50-60 ℃, wherein the purity is 99.5%, and the yield is 81.5%.
(2) Synthesis of Li Feisi t (Compound E) of the present invention
TABLE 8 Main raw materials and reagents for synthesizing Li Feisi dtex (Compound E) of the invention
The preparation method comprises the following steps:
A. 15.2g of compound C, 14.8g of HATU and 76mL of THF are added into a 500mL triangular flask, stirring is started, and the temperature is reduced to 0-10 ℃ in an ice water bath;
B. after stirring uniformly, preserving heat, dropwise adding 5.0g of DIPEA at 0-10 ℃, naturally returning to 20-30 ℃ after dropwise adding, reacting for 15+/-2 h, and performing HPLC (high performance liquid chromatography) central control reaction, wherein the intermediate compound is obtained after the reaction is completed when the content of the compound C is less than 0.1%;
C. 10.9g of Compound D, 16.6. 16.6g K are added in a 1L beaker 3 PO 4 ·7H 2 O and 150mL of pure water are stirred until the solid is completely dissolved, thus obtaining a standby liquid for standby;
D. slowly adding the standby liquid in the C into the intermediate compound by dropwise adding at the temperature of 0-10 ℃, naturally returning to the temperature of 20-30 ℃ for reacting for 15+/-2 h, and performing intermediate compound less than 0.1% by HPLC (high performance liquid chromatography). The reaction is finished, and a reaction liquid is obtained;
E. post-treatment: adjusting the pH of the reaction solution to 2-3 by using 5N hydrochloric acid, separating, extracting the lower aqueous phase by using 60mL ethyl acetate/tetrahydrofuran extract (EA: THF=1:1) for 1 time, merging the organic phases, washing the organic phases by using 60mL saturated saline for 1 time, concentrating under reduced pressure to dryness to obtain a crude product, and concentrating the upper organic phase under reduced pressure to dryness to obtain the crude product;
F. purifying a crude product: the crude products are dissolved in NaOH aqueous solution (2.7 g NaOH+300mL pure water) after being combined, the mixture is filtered by a filter membrane, the pH of the filtrate is regulated to 2-4 by 5N hydrochloric acid, the mixture is stirred and crystallized for 2+ -1 h, the product is obtained after filtration, and the mixture is dried to constant weight by a decompression drying oven at 50-60 ℃ to obtain 17.1g of compound E (Li Feisi T), white solid with the purity of 99.7 percent and the yield of 81.4 percent.
Example 5 Synthesis method of Li Feisi Te of the invention
(1) Synthesis of Compound C
TABLE 9 Main raw materials and reagents for synthesizing Compound C
The preparation method comprises the following steps:
1) 15.0g of compound B, 35.2g of compound A and 150mL of THF are sequentially added into a 500mL reaction bottle, stirring is started, and ice water bath is cooled to 0-10 ℃;
2) After uniformly stirring, slowly dripping 64.4g of DIPEA, controlling the temperature to be 0-10 ℃ in the dripping process, preserving the temperature to be 0-10 ℃ after dripping, reacting for 1-2 h, and controlling the reaction by HPLC (high performance liquid chromatography), wherein the reaction is completed when the content of the compound B is less than 0.5%;
3) After the reaction is finished, the pH of the reaction solution is regulated to 1-2 by 2N hydrochloric acid under stirring, a large amount of solids are separated out, the temperature is reduced to 0-10 ℃, stirring crystallization is carried out for 1-2 hours, a filter cake is obtained by filtering, the filter cake is washed once by 30mL of pure water, and is washed once by 30mL of THF, and the compound C is obtained by drying under reduced pressure at 50-60 ℃ to obtain 26.9g of a compound C product with the purity of 99.4 percent and the yield of 83.0 percent.
(2) Synthesis of Li Feisi t (Compound E) of the present invention
TABLE 10 Main raw materials and reagents for synthesizing Li Feisi dtex (Compound E) of the invention
The preparation method comprises the following steps:
A. 15.2g of compound C, 14.8g of HATU and 152mL of THF are added into a 500mL triangular flask, stirring is started, and the temperature is reduced to 0-10 ℃ by ice water bath;
B. after stirring uniformly, dropwise adding 20.2g of DIPEA at the temperature of 0-10 ℃, naturally returning to the temperature of 20-30 ℃ after the dropwise adding is completed, reacting for 15+/-2 h, and performing HPLC (high performance liquid chromatography) central control reaction, wherein the intermediate compound is obtained after the reaction is completed when the compound C is less than 0.1%;
C. 21.8g of Compound D, 41.4. 41.4g K are added in a 1L beaker 3 PO 4 ·7H 2 O and 150mL of pure water are stirred until the solid is completely dissolved, thus obtaining a standby liquid for standby;
D. slowly adding the standby liquid in the C into an intermediate compound by dripping at the temperature of 0-10 ℃, naturally returning to the temperature of 20-30 ℃ for reacting for 15+/-2 hours, and performing a medium-control reaction by HPLC (high performance liquid chromatography), wherein the intermediate compound is less than 0.1% after the reaction is finished, so as to obtain a reaction liquid;
E. post-treatment: adjusting the pH of the reaction solution to 2-3 by using 5N hydrochloric acid, separating, extracting the lower aqueous phase by using 60mL ethyl acetate/tetrahydrofuran extract (EA: THF=1:1) for 1 time, merging the organic phases, washing the organic phases by using 60mL saturated saline for 1 time, concentrating under reduced pressure to dryness to obtain a crude product, and directly concentrating the upper organic phase under reduced pressure to dryness to obtain the crude product;
F. purifying a crude product: the crude products are dissolved in NaOH aqueous solution (2.7 g NaOH+300mL pure water) after being combined, the mixture is filtered by a filter membrane, the pH of the filtrate is regulated to 2-4 by 5N hydrochloric acid, the mixture is stirred and crystallized for 2+ -1 h, the product is obtained after filtration, and the mixture is dried to constant weight by a decompression drying oven at 50-60 ℃ to obtain 17.6g of compound E (Li Feisi t), white solid with purity of 99.7 percent and yield of 83.8 percent.
The advantageous effects of the present invention are described below by way of test examples.
Test example 1 detection of Lifeprist obtained by the preparation method of the present invention
The example 2 method was used to prepare leflunomide, which was subjected to hydrogen spectrometry and mass spectrometry detection, and compared with the Li Feisi specification standard spectrum in the literature. 1 HNMR and MS spectra are shown in fig. 1 and fig. 2, respectively.
Example 2 preparation of leflunomide 1 HNMR and MS spectra were resolved as follows:
MS:M+H＝615
1 HNMR7.83(1H,s),7.71(1H,s),7.69(1H,d,J＝3.9Hz),7.61(1H,d,J＝6Hz),7.55(2H,m),7.41(1H,t,J＝6Hz),7.27(1H,t,J＝6Hz),7.14(1H,s),7.03(1H,d,J＝9Hz),6.81(1H,s),5.11(1H,t,J＝5.1Hz),4.73(2H,br),3.71(2H,br),3.38(1H,m),3.21(1H,m),2.95(3H,s),2.79(2H,s)
the product patterns 1 and 2 obtained in example 2 of the present invention are identical to those of Li Feisi dtex literature patterns 3 and 4, respectively, and thus the product obtained in example 2 is Li Feisi dtex.
In summary, the synthesis method of Li Feisi has short synthesis route, compared with the prior art, reaction steps such as protection and deprotection on functional groups are reduced, chiral structures are introduced only in the last step, the configuration remains unchanged in the reaction, and racemization risk of chiral carbon atoms in the reaction process is reduced; the reaction condition is mild, the solvent type and side reaction are less, and heavy metals such as palladium are not used as catalysts in the synthesis process, so that the method is environment-friendly and the cost is reduced; meanwhile, the total yield of the whole reaction route is high, and the method is favorable for large-scale industrial production.
Claims (1)
1. A synthesis method of leflunomide is characterized by comprising the following steps: the method comprises the following steps:
(1) Synthesis of Compound C:
1) 15g of compound B, 23.5g of compound A and 150mL of THF are sequentially added into a 500mL reaction bottle, stirring is started, and ice water bath is cooled to 0-10 ℃;
2) After uniformly stirring, slowly dripping 43.0g of DIPEA, controlling the temperature to be 0-10 ℃ in the dripping process, preserving the temperature to be 0-10 ℃ after dripping, reacting for 1-2 h, and controlling the reaction by HPLC (high performance liquid chromatography), wherein the reaction is completed when the content of the compound B is less than 0.5%;
3) After the reaction is finished, the pH of the reaction solution is regulated to 1-3 by 2N hydrochloric acid under stirring, a large amount of solids are separated out, the temperature is reduced to 0-10 ℃, stirring crystallization is carried out for 1-2 hours, a filter cake is obtained by filtering, the filter cake is washed once by 30mL of pure water, and is washed once by 30mL of THF, and 29.2g of compound C product is obtained by drying under reduced pressure at 50-60 ℃, wherein the purity is 99.6%, and the yield is 90.1%;
(2) Li Feisi synthesis:
A. 15.2g of compound C, 14.8g of HATU and 152mL of THF are added into a 500mL triangular flask, stirring is started, and the temperature is reduced to 0-10 ℃ by ice water bath;
B. after stirring uniformly, preserving heat, dropwise adding 6.1g of DIPEA at 0-10 ℃, naturally returning to 20-30 ℃ after dropwise adding, reacting for 15+/-2 h, and performing HPLC (high performance liquid chromatography) central control reaction, wherein the intermediate compound is obtained after the reaction is completed when the content of the compound C is less than 0.1%;
C. in a 1L beaker was added 19.8g of Compound D, 39.5g K 3 PO 4 ·7H 2 O and 150mL of pure water are stirred until the solid is completely dissolved, thus obtaining a standby liquid for standby;
D. slowly adding the standby liquid in the C into an intermediate compound by dripping at the temperature of 0-10 ℃, naturally returning to the temperature of 20-30 ℃ for reacting for 15+/-2 hours, and performing a medium-control reaction by HPLC (high performance liquid chromatography), wherein the intermediate compound is less than 0.1% after the reaction is finished, so as to obtain a reaction liquid;
E. post-treatment: regulating the pH of the reaction solution to 2-3 by using 5N hydrochloric acid, separating, extracting the lower aqueous phase by using 60mL ethyl acetate/tetrahydrofuran extract for 1 time, washing the organic phase by using 60mL saturated saline water for 1 time after combining the organic phases, concentrating under reduced pressure to dryness to obtain a crude product, and directly concentrating the upper organic phase under reduced pressure to dryness to obtain the crude product;
F. purifying a crude product: and (3) mixing the crude products, dissolving the crude products in NaOH aqueous solution, filtering the mixture by using a filter membrane, regulating the pH value of the filtrate to 2-4 by using 5N hydrochloric acid, stirring for crystallization for 2+/-1 h, filtering the mixture to obtain a product, and drying the product in a reduced pressure drying box at 50-60 ℃ until the weight is constant to obtain 19g of compound E, wherein the purity of the white solid is 99.7%, and the yield is 90.5%.
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| WO2019004936A1 (en) * | 2017-06-30 | 2019-01-03 | Scinopharm Taiwan, Ltd. | Process for preparing lifitegrast and intermediates thereof |
| WO2019026014A1 (en) * | 2017-08-03 | 2019-02-07 | Dr. Reddy's Laboratories Limited | Processes for preparation of lifitegrast and intermediates thereof |
| WO2019043724A1 (en) * | 2017-08-28 | 2019-03-07 | Msn Laboratories Private Limited, R&D Center | Processes for the preparation of (s)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl) propanoic acid and polymorphs thereof |
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| WO2019004936A1 (en) * | 2017-06-30 | 2019-01-03 | Scinopharm Taiwan, Ltd. | Process for preparing lifitegrast and intermediates thereof |
| WO2019026014A1 (en) * | 2017-08-03 | 2019-02-07 | Dr. Reddy's Laboratories Limited | Processes for preparation of lifitegrast and intermediates thereof |
| WO2019043724A1 (en) * | 2017-08-28 | 2019-03-07 | Msn Laboratories Private Limited, R&D Center | Processes for the preparation of (s)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl) propanoic acid and polymorphs thereof |
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Application publication date: 20201009 Assignee: Sichuan meiyugao Biomedical Technology Co.,Ltd. Assignor: CHENGDU WEIBANG PHARMACEUTICAL Co.,Ltd. Contract record no.: X2023980054097 Denomination of invention: A synthesis method of Levofloxacin Granted publication date: 20231010 License type: Common License Record date: 20231227 |