CN111747941A - Synthesis method of lifustat - Google Patents
Synthesis method of lifustat Download PDFInfo
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- CN111747941A CN111747941A CN201910251924.1A CN201910251924A CN111747941A CN 111747941 A CN111747941 A CN 111747941A CN 201910251924 A CN201910251924 A CN 201910251924A CN 111747941 A CN111747941 A CN 111747941A
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- 238000001308 synthesis method Methods 0.000 title abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 106
- 230000002829 reductive effect Effects 0.000 claims abstract description 45
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 41
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 39
- 238000000034 method Methods 0.000 claims abstract description 34
- 239000002904 solvent Substances 0.000 claims abstract description 20
- 230000008569 process Effects 0.000 claims abstract description 12
- 239000003054 catalyst Substances 0.000 claims abstract description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 81
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 64
- 150000001875 compounds Chemical class 0.000 claims description 48
- 238000003756 stirring Methods 0.000 claims description 48
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 46
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 40
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 39
- 239000012043 crude product Substances 0.000 claims description 39
- 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 38
- 239000000243 solution Substances 0.000 claims description 28
- 238000001914 filtration Methods 0.000 claims description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- 238000001035 drying Methods 0.000 claims description 23
- 238000005406 washing Methods 0.000 claims description 21
- 239000002253 acid Substances 0.000 claims description 20
- 239000007787 solid Substances 0.000 claims description 19
- 239000012074 organic phase Substances 0.000 claims description 18
- 238000001816 cooling Methods 0.000 claims description 17
- 239000007788 liquid Substances 0.000 claims description 17
- 229940126062 Compound A Drugs 0.000 claims description 16
- 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 16
- 239000012065 filter cake Substances 0.000 claims description 14
- 239000007821 HATU Substances 0.000 claims description 12
- 230000035484 reaction time Effects 0.000 claims description 12
- 229910019142 PO4 Inorganic materials 0.000 claims description 11
- 238000002425 crystallisation Methods 0.000 claims description 11
- 230000008025 crystallization Effects 0.000 claims description 11
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical group [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 8
- 239000010452 phosphate Substances 0.000 claims description 8
- 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
- 238000000605 extraction Methods 0.000 claims description 6
- 238000000746 purification Methods 0.000 claims description 5
- 239000011259 mixed solution Substances 0.000 claims description 4
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 4
- 235000011009 potassium phosphates Nutrition 0.000 claims description 4
- 230000006837 decompression Effects 0.000 claims description 2
- 239000012071 phase Substances 0.000 claims description 2
- 239000008213 purified water Substances 0.000 claims description 2
- 239000001488 sodium phosphate Substances 0.000 claims description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 abstract description 12
- 229910052763 palladium Inorganic materials 0.000 abstract description 6
- 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
- 239000000047 product Substances 0.000 description 44
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- 238000004128 high performance liquid chromatography Methods 0.000 description 25
- 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 description 16
- 239000003153 chemical reaction reagent Substances 0.000 description 13
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- 208000003556 Dry Eye Syndromes Diseases 0.000 description 7
- 108010064548 Lymphocyte Function-Associated Antigen-1 Proteins 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- 102100022339 Integrin alpha-L Human genes 0.000 description 5
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- 108010064593 Intercellular Adhesion Molecule-1 Proteins 0.000 description 5
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- 239000000706 filtrate Substances 0.000 description 5
- 239000012528 membrane Substances 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
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- 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
- -1 methyl sulfo group Chemical group 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 2
- CGXSFPJGZFRGNL-UHFFFAOYSA-N 5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid hydrochloride Chemical group Cl.OC(=O)c1c(Cl)cc2CNCCc2c1Cl CGXSFPJGZFRGNL-UHFFFAOYSA-N 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
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
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- 238000011161 development Methods 0.000 description 1
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
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- 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
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- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000003960 inflammatory cascade Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229960005381 lifitegrast Drugs 0.000 description 1
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Images
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
Abstract
The invention provides a synthesis method of lifustt. The synthesis method of the invention is simple and short in synthetic route, compared with the prior art, the reaction steps of protection and deprotection on functional groups are reduced, the chiral structure is introduced only in the last step, the configuration is kept unchanged in the reaction, and the racemization risk of chiral carbon atoms in the reaction process is reduced; the reaction condition is mild, the types of solvents and side reactions are less, and heavy metals such as palladium and the like are not used as catalysts in the synthesis process, so that the method is green and 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 lifitest, in particular to a chemical synthesis method of lifitest bulk drug (lifitest), belonging to the technical field of chemical synthesis processes.
Background
With the vigorous development of the communication industry, the cell phone party and the low head family which are seen everywhere are promoted, and the daily eye use strength is improved. The existing survey data show that the dry eye disease risk is gradually increased with the age: the prevalence rate of the population of 30-40 years old is more than 20%; the prevalence rate of people over 70 years old is as high as 36.1%; while the incidence rate of male patients is 14.9%; the incidence of female patients is 22.8%. In addition, with the spread of devices such as mobile phones and computers, the incidence of dry eye in young people has also increased year by year, and thus ophthalmic diseases represented by dry eye have been on the increasing epidemic trend. Worldwide, the incidence of dry eye disease accounts for about 5% -34% of the total population, and the higher the living standard, the more popular the electronic products and the higher the usage rate of the electronic products, the higher the incidence.
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 cells and endothelial cells after inflammation. LFA-1 binds to ICAM-1 and initiates homing and activation of ocular surface T cells and subsequent cytokine release, leading to local inflammation. This mechanism plays a role in the inflammatory cascade of dry eye, and therefore inhibitors of LFA-1/ICAM-1 interaction reduce the level of ocular surface T-cell mediated inflammation by inhibiting the binding of the two.
Lifitester (Lifitegrast) developed by Shire corporation, uk, is the first approved small molecule LFA-1/ICAM-1 interaction antagonist on the market worldwide and was approved by the FDA for the treatment of signs and symptoms of dry eye, under the trade name Xiidra, 7 months in 2016. This is the first new drug approved by FDA for treating dry eye disease, which is an antagonist of lymphocyte function-associated antigen 1(LFA-1), and its chemical structural formula is:
currently, there are three main routes of the synthesis published by lifaste in WO2014018748a1, as follows:
route one:
in the reaction process of the first route, amino and carboxyl protecting groups are introduced, 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 the racemization probability of a chiral center is increased, and the ee% value becomes the key point to be controlled in the reaction process; and heavy metals such as palladium and the like are introduced in the reaction process, so that the method is harmful to human bodies and the environment.
And a second route:
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 protective groups of amino and carboxyl introduced in the reaction process, thereby prolonging the production period, increasing the production cost and not meeting the requirement of green chemistry; the heavy metals such as palladium and the like are introduced, so that the defects of harm to human bodies and environment are caused.
And a third route:
compared with the first route and the second route, the third route has more reaction steps, and the reaction in the first methyl sulfo group step is reversible and not easy to purify while having all the defects of the first route and the second route, so that the yield is low, and the production cost is greatly increased.
In conclusion, the preparation of the lifaste in the prior art faces the problems of complex reaction process, difficult purification of products, low yield, long production period, high cost, great harm to human bodies and environment and the like. Therefore, a synthesis method of liffetiliast with simple preparation, low cost, environmental protection and high yield is urgently needed.
Disclosure of Invention
In order to solve the above problems, the present invention provides a method for synthesizing lifaste, comprising the following steps:
step 1: uniformly stirring the compound A and the compound B in a solvent, adding DIPEA for reaction, and purifying reaction liquid obtained by the reaction to obtain a compound C;
step 2: uniformly stirring the compound C and HATU in a solvent, adding DIPEA for reaction, and obtaining an intermediate state after the reaction is finished;
and step 3: dissolving the compound D and soluble phosphate in pure water to obtain a standby solution; and adding the solution to be used into the intermediate state for reaction, and purifying the reaction solution 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-to-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, the compound D, HATU, DIPEA and soluble phosphate is 1: 1-2: 1-4: 2-5; the weight-to-volume ratio of the compound C to the solvent is 1: 5-20 (w/v); the weight-to-volume ratio of the compound D to 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 the compound C, the compound D, HATU, DIPEA and soluble phosphate is 1:1.5:1:1.5: 3; the weight to 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 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 slowly added dropwise; the temperature of the whole process in the step 1 is 0-10 ℃; the reaction time is 1-3 h; after the pH value is adjusted to 1-4 by strong acid, cooling and crystallizing, filtering, washing a filter cake, and drying under reduced pressure; wherein the strong acid is sulfuric acid or hydrochloric acid.
Further, in the step 1, the temperature of the whole process of the step 1 is 5 ℃; the reaction time is 2 h; the purification is that pH is adjusted to 3 by strong acid, the temperature is reduced to 0-10 ℃ for crystallization, the filtration is carried out, a filter cake is washed once by purified water and tetrahydrofuran respectively, and the decompression drying is carried out for 1-3 h at 50-60 ℃; wherein the strong acid is hydrochloric acid.
Further, in the step 2, the DIPEA is slowly added dropwise; the stirring and DIPEA adding temperature is 0-10 ℃, and the reaction temperature after the dripping is 20-30 ℃; the reaction time is 15-30 h.
Further, in the step 2, the temperature for stirring and dripping DIPEA is 5 ℃, and the reaction temperature after dripping is 25 ℃; the reaction time is 20 h.
Further, in the step 3, the step of adding the standby liquid into the intermediate state is to slowly dropwise add the standby liquid into the intermediate state; the temperature of the solution to be added is 0-10 ℃, and the reaction temperature after the dropwise addition is 20-30 ℃; the reaction time is 15-30 h; the purification comprises the steps of adjusting the pH value to 2-4 by using strong acid, separating liquid, extracting the lower-layer water phase, combining organic phases, washing, concentrating under reduced pressure to dryness to obtain a crude product, directly concentrating the upper-layer organic phase under reduced pressure to dryness to obtain a crude product, dissolving the combined crude product, filtering, adjusting the pH value to 2-4 by using strong acid, stirring for crystallization 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 using a mixed solution of 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 liquid to be used is 5 ℃, and the reaction temperature after the dropwise adding is 25 ℃; the reaction time is 20 h; after the pH value of the purified solution is adjusted to 3 by strong acid, separating the solution, extracting the lower aqueous phase, combining the organic phases, washing by saturated saline solution, concentrating under reduced pressure to dryness to obtain a crude product, directly concentrating the upper organic phase under reduced pressure to dryness to obtain a crude product, dissolving the combined crude product, filtering, adjusting the pH value to 3 by strong acid, stirring for crystallization for 2 hours, filtering to obtain a solid, and drying under reduced pressure at 50-60 ℃ to constant weight; wherein the strong acid is hydrochloric acid; the extraction is the extraction of a mixed solution of ethyl acetate and tetrahydrofuran, and the volume ratio of the ethyl acetate to the tetrahydrofuran is 1:1.
In the present invention w/v represents the mass to volume ratio in g/ml.
The synthesis method of the invention is simple and short in synthetic route, compared with the prior art, the reaction steps of protection and deprotection on functional groups are reduced, the chiral structure is introduced only in the last step, the configuration is kept unchanged in the reaction, and the racemization risk of chiral carbon atoms in the reaction process is reduced; the reaction condition is mild, the types of solvents and side reactions are less, and heavy metals such as palladium and the like are not used as catalysts in the synthesis process, so that the method is green and 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.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Drawings
FIG. 1 shows the product obtained in example 21HNMR atlas.
FIG. 2 is an ESI-MS spectrum of the product obtained in example 2.
FIG. 3 is a schematic representation of liflstet1HNMR literature map.
FIG. 4 is an ESI-MS literature profile of lifustt.
Detailed Description
1. The chemical names and sources of the main raw materials and the solvent reagents used in the specific embodiment of the invention are as follows:
a compound A: the chemical name is 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline-6-carboxylic acid hydrochloride, which is provided by Pont pharmaceutical industry Co.
Compound B: the chemical name is benzofuran-6-formyl chloride, which is provided by Pont pharmaceutical industry 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 Nippon pharmaceutical Co.
Compound E prepared according to the invention: and (3) carrying out Lifetid reaction.
HATU: the chemical name is 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate, and the product is produced by a chemical reagent factory of Chengdulong.
DIPEA: the chemical name is N, N-diisopropylethylamine, produced by Chengdu Kelong chemical reagent factory.
THF: the chemical name is tetrahydrofuran, produced by Beijing Miruida technologies, Inc.
Other raw materials and equipment used in the embodiment of the present invention are known products and obtained by purchasing commercially available products.
2. The general synthetic route for preparing the liffetid is as follows:
example 1 Synthesis of Lifetilide of the invention
(1) Synthesis of Compound C
TABLE 1 Main raw materials and reagents for the Synthesis of Compound C
The preparation method comprises the following steps:
1) sequentially adding 2.0g of compound A, 1.3g of compound B and 10mL of THF into a 25mL reaction bottle, starting stirring, and cooling to 5 +/-2 ℃ in an ice-water bath;
2) after stirring uniformly, slowly dropwise adding 1.9g of DIPEA, controlling the temperature to be 5 +/-2 ℃ in the dropwise adding process, and then preserving the temperature to be 5 +/-2 ℃ for reacting for 2 hours; performing HPLC (high performance liquid chromatography) controlled reaction, wherein the reaction is finished when the content of the compound B is less than 0.5%;
3) after the reaction is finished, adjusting the pH of the reaction solution to 2 by using 2N hydrochloric acid under stirring, separating out a large amount of solid, cooling to 0 ℃, stirring and crystallizing for 2 hours, filtering to obtain a filter cake, washing the filter cake once by using 5mL of pure water, washing once by using 5mL of THF, and drying under reduced pressure at 50-60 ℃ to obtain 2.47g of a compound C with the purity of 99.4% and the yield of 89.5%.
(2) Synthesis of Lifetid (Compound E) of the invention
TABLE 2 Main raw materials and reagents for the synthesis of Lifexistat (Compound E) according to the invention
The preparation method comprises the following steps:
A. adding 1.5g of compound C, 1.5g of HATU and 7mL of THF into a 10mL triangular flask, starting stirring, and cooling to 0-10 ℃ in an ice-water bath;
B. after stirring uniformly, keeping the temperature at 0-10 ℃, dropwise adding 0.5g of DIPEA, after completely dropwise adding, naturally returning the temperature to 20-30 ℃ for reaction for 15 +/-2 h, and after the reaction is controlled by HPLC, finishing the reaction when the content of the compound C is less than 0.1%, thus obtaining an intermediate compound;
C. a10 mL beaker was charged with 1.1g of Compound D, 5.2g K3PO4·7H2O and 15mL of pure water are stirred until the solid is completely dissolved to obtain a standby liquid for standby;
D. controlling the temperature to be 0-10 ℃, slowly dripping the standby liquid in the step C into the intermediate compound, completely dripping, naturally returning the temperature to 20-30 ℃ for reaction for 15 +/-2 hours, and performing HPLC (high performance liquid chromatography) controlled reaction until the intermediate compound is less than 0.1%, namely, the reaction is finished, thus obtaining a reaction liquid;
E. and (3) post-treatment: adjusting the pH of the reaction solution to 2-3 with 2N hydrochloric acid, separating the solution, extracting the lower aqueous phase with 10mL ethyl acetate/tetrahydrofuran extract (EA: THF ═ 1:1) for 1 time, combining the organic phases, washing with 10mL saturated saline solution 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 a crude product;
F. and (3) purifying a crude product: and (3) combining the crude products, dissolving the combined crude products in NaOH aqueous solution (0.3g of NaOH +30ml of pure water), filtering the obtained product through a filter membrane, adjusting the pH of the filtrate to 2-4 by using 2N hydrochloric acid, stirring the obtained product for crystallization for 2 +/-1 h, filtering the obtained product to obtain a product, and drying the product in a reduced pressure drying oven at the temperature of 50-60 ℃ until the weight of the product is constant to obtain 2.0g of a compound E (lifaste) which is a white solid and has the purity of 99.7% and the yield of.
Example 2 Synthesis of Lifetilide of the invention
(1) Synthesis of Compound C
TABLE 3 Synthesis of Compound C Main raw materials and reagents
The preparation method comprises the following steps:
1) adding 15g of the compound B, 23.5g of the compound A and 150mL of THF in a 500mL reaction bottle in sequence, starting stirring, and cooling to 0-10 ℃ in an ice water bath;
2) after stirring uniformly, slowly dropwise adding 43.0g of DIPEA, controlling the temperature to be 0-10 ℃ in the dropwise adding process, preserving the temperature to be 0-10 ℃ after dropwise adding, reacting for 1-2 h, and performing HPLC (high performance liquid chromatography) controlled reaction until the content of the compound B is less than 0.5%, namely the reaction is finished;
3) after the reaction is finished, regulating the pH of the reaction solution to 1-3 with 2N hydrochloric acid under stirring, separating out a large amount of solid, cooling to 0-10 ℃, stirring and crystallizing for 1-2 h, filtering to obtain a filter cake, washing the filter cake with 30mL of pure water once, washing with 30mL of THF once, and drying at 50-60 ℃ under reduced pressure to obtain 29.2g of a compound C product with the purity of 99.6% and the yield of 90.1%.
(2) Synthesis of Lifetid (Compound E) of the invention
TABLE 4 Main raw materials and reagents for the synthesis of Lifexistat (Compound E) according to the invention
A. Adding 15.2g of compound C, 14.8g of HATU and 152mL of THF into a 500mL triangular flask, starting stirring, and cooling to 0-10 ℃ in an ice-water bath;
B. after stirring uniformly, keeping the temperature at 0-10 ℃, dropwise adding 6.1g of DIPEA, after completely dropwise adding, naturally returning the temperature to 20-30 ℃ for reaction for 15 +/-2 h, and after the reaction is controlled by HPLC, finishing the reaction when the content of the compound C is less than 0.1%, thus obtaining an intermediate compound;
C. 19.8g of Compound D, 39.5g K were added to a 1L beaker3PO4·7H2O and 150mL of pure water are stirred until the solid is completely dissolved to obtain a standby liquid for standby;
D. controlling the temperature to be 0-10 ℃, slowly dripping the standby liquid in the step C into the intermediate compound, completely dripping, naturally returning the temperature to 20-30 ℃ for reaction for 15 +/-2 hours, and performing HPLC (high performance liquid chromatography) controlled reaction until the intermediate compound is less than 0.1%, namely, the reaction is finished, thus obtaining a reaction liquid;
E. and (3) post-treatment: adjusting the pH of the reaction solution to 2-3 with 5N hydrochloric acid, separating the solution, extracting the lower aqueous phase with 60mL of ethyl acetate/tetrahydrofuran extract (EA: THF ═ 1:1) for 1 time, combining the organic phases, washing with 60mL of saturated saline solution for 1 time, concentrating under reduced pressure until the crude product is obtained, and directly concentrating the upper organic phase under reduced pressure until the crude product is obtained;
F. and (3) purifying a crude product: and (3) combining the crude products, dissolving the combined crude products in NaOH aqueous solution (2.7g of NaOH +300mL of pure water), filtering the obtained product with a filter membrane, adjusting the pH of the filtrate to 2-4 by using 5N hydrochloric acid, stirring the obtained product for crystallization for 2 +/-1 h, filtering the obtained product to obtain a product, and drying the product in a reduced pressure drying oven at the temperature of 50-60 ℃ until the weight of the product is constant to obtain 19g of a compound E (lifaste) which is a white solid and has the purity of 99.7% and the yield of.
Example 3 Synthesis of Lifetilide of the invention
(1) Synthesis of Compound C
TABLE 5 Main raw materials and reagents for the Synthesis of 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 (tetrahydrofuran) into a 1000mL reaction bottle, starting stirring, and cooling to 0-10 ℃ in an ice water bath;
2) after stirring uniformly, slowly dropwise adding 143.2g of DIPEA, controlling the temperature to be 0-10 ℃ in the dropwise adding process, preserving the temperature to be 0-10 ℃ after dropwise adding, reacting for 1-2 h, and performing HPLC (high performance liquid chromatography) controlled reaction until the content of the compound B is less than 0.5%, namely the reaction is finished;
3) after the reaction is finished, regulating the pH of the reaction solution to 1-2 with 2N hydrochloric acid under stirring, precipitating a large amount of solid, cooling to 0-10 ℃, stirring and crystallizing for 1-2 hours, filtering to obtain a filter cake, washing the filter cake once with 100mL of pure water, washing once with 100mL of THF, and drying under reduced pressure at 50-60 ℃ to obtain 98.1g of a compound C product with the purity of 99.5% and the yield of 90.8%.
(2) Synthesis of Lifetid (Compound E) of the invention
TABLE 6 Main raw materials and reagents for the synthesis of Lifexistat (Compound E) according to the invention
The preparation method comprises the following steps:
A. adding 85g of compound C, 82.83g of HATU and 850mL of THF into a 3000mL triangular flask, starting stirring, and cooling to 0-10 ℃ in an ice-water bath;
B. after stirring uniformly, keeping the temperature at 0-10 ℃, dropwise adding 42.23 DIPEA, after completely dropwise adding, naturally returning the temperature to 20-30 ℃ for reaction for 15 +/-2 h, and after the reaction is controlled by HPLC, finishing the reaction when the content of the compound C is less than 0.1% to obtain an intermediate compound;
C. to a 2000ml beaker was added 72.12g of Compound D, 161.83g K3PO4·7H2Stirring O and 850mL of pure water until the solid is completely dissolved to obtain a standby liquid for standby;
D. controlling the temperature to be 0-10 ℃, slowly dripping the standby liquid in the step C into the intermediate compound, completely dripping, naturally returning the temperature to 20-30 ℃ for reaction for 15 +/-2 hours, and performing HPLC (high performance liquid chromatography) controlled reaction until the intermediate compound is less than 0.1%, namely, the reaction is finished, thus obtaining a reaction liquid;
E. and (3) post-treatment: adjusting the pH of the reaction solution to 2-3 with 2N hydrochloric acid, separating the solution, extracting the lower aqueous phase with 340mL of ethyl acetate/tetrahydrofuran extract (EA: THF ═ 1:1) for 1 time, combining the organic phases, washing with 340mL of saturated saline solution for 1 time, concentrating under reduced pressure until the crude product is dried to obtain a crude product, and directly concentrating the upper organic phase under reduced pressure until the crude product is dried to obtain the crude product;
F. and (3) purifying a crude product: and (3) combining the crude products, dissolving the combined crude products in NaOH aqueous solution (17.43g of NaOH +1700mL of pure water), filtering the obtained product through a filter membrane, adjusting the pH of the filtrate to 2-4 by using 2N hydrochloric acid, stirring the obtained product for crystallization for 2 +/-1 h, filtering the obtained product to obtain a product, and drying the product in a reduced pressure drying oven at the temperature of 50-60 ℃ until the weight of the product is constant to obtain 111.95g of compound E (lifaste) which is a white solid and has the purity of 99.5% and the yield of 83.
Example 4 Synthesis of Lifetilide of the invention
(1) Synthesis of Compound C
TABLE 7 Main raw materials and reagents for the Synthesis of Compound C
The preparation method comprises the following steps:
1) adding 15g of the compound B, 4.7g of the compound A and 150mL of THF in a 500mL reaction bottle in sequence, starting stirring, and cooling to 0-10 ℃ in an ice water bath;
2)2) after uniformly stirring, slowly dripping 21.5g of DIPEA, controlling the temperature to be 0-10 ℃ in the dripping process, preserving the temperature to be 0-10 ℃ after finishing dripping, reacting for 1-2 h, and performing HPLC (high performance liquid chromatography) controlled reaction until the content of the compound B is less than 0.5%, namely finishing the reaction;
3) after the reaction is finished, regulating the pH of the reaction solution to 1-2 with 2N hydrochloric acid under stirring, precipitating a large amount of solid, cooling to 0-10 ℃, stirring and crystallizing for 1-2 hours, filtering to obtain a filter cake, washing the filter cake with 30mL of pure water once, washing with 30mL of THF once, and drying at 50-60 ℃ under reduced pressure to obtain 26.4g of a compound C product with the purity of 99.5% and the yield of 81.5%.
(2) Synthesis of Lifetid (Compound E) of the invention
TABLE 8 Main raw materials and reagents for the synthesis of Lifexistat (Compound E) according to the invention
The preparation method comprises the following steps:
A. adding 15.2g of compound C, 14.8g of HATU and 76mL of THF into a 500mL triangular flask, starting stirring, and cooling to 0-10 ℃ in an ice-water bath;
B. after stirring uniformly, keeping the temperature at 0-10 ℃, dropwise adding 5.0g of DIPEA, after completely dropwise adding, naturally returning the temperature to 20-30 ℃ for reaction for 15 +/-2 h, and after the reaction is controlled by HPLC, finishing the reaction when the content of the compound C is less than 0.1%, thus obtaining an intermediate compound;
C. 10.9g of Compound D, 16.6g K were added to a 1L beaker3PO4·7H2O and 150mL of pure water are stirred until the solid is completely dissolved to obtain a standby liquid for standby;
D. and controlling the temperature to be 0-10 ℃, slowly dripping the solution to be used in the C into the intermediate compound, completely dripping, naturally returning the temperature to 20-30 ℃, reacting for 15 +/-2 hours, and performing HPLC (high performance liquid chromatography) controlled reaction to obtain less than 0.1% of the intermediate compound. Namely, reaction liquid is obtained after the reaction is finished;
E. and (3) post-treatment: adjusting the pH of the reaction solution to 2-3 with 5N hydrochloric acid, separating the solution, extracting the lower aqueous phase with 60mL ethyl acetate/tetrahydrofuran extract (EA: THF ═ 1:1) for 1 time, combining the organic phases, washing with 60mL saturated saline solution 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 a crude product;
F. and (3) purifying a crude product: and (3) combining the crude products, dissolving the combined crude products in NaOH aqueous solution (2.7g of NaOH +300mL of pure water), filtering the obtained product with a filter membrane, adjusting the pH of the filtrate to 2-4 by using 5N hydrochloric acid, stirring the obtained product for crystallization for 2 +/-1 h, filtering the obtained product to obtain a product, and drying the product in a reduced pressure drying oven at the temperature of 50-60 ℃ until the weight of the product is constant to obtain 17.1g of a compound E (lifaste) which is a white solid and has the purity of 99.7% and the yield of.
Example 5 Synthesis of Lifetilide of the invention
(1) Synthesis of Compound C
TABLE 9 Main raw materials and reagents for the Synthesis of Compound C
The preparation method comprises the following steps:
1) adding 15.0g of compound B, 35.2g of compound A and 150mL of THF in a 500mL reaction bottle in sequence, starting stirring, and cooling to 0-10 ℃ in an ice-water bath;
2) after stirring uniformly, slowly dropwise adding 64.4g of DIPEA, controlling the temperature to be 0-10 ℃ in the dropwise adding process, preserving the temperature to be 0-10 ℃ after dropwise adding, reacting for 1-2 h, and performing HPLC (high performance liquid chromatography) controlled reaction until the content of the compound B is less than 0.5%, namely the reaction is finished;
3) after the reaction is finished, regulating the pH of the reaction solution to 1-2 with 2N hydrochloric acid under stirring, precipitating a large amount of solid, cooling to 0-10 ℃, stirring and crystallizing for 1-2 hours, filtering to obtain a filter cake, washing the filter cake with 30mL of pure water once, washing with 30mL of THF once, and drying at 50-60 ℃ under reduced pressure to obtain 26.9g of a compound C product with the purity of 99.4% and the yield of 83.0%.
(2) Synthesis of Lifetid (Compound E) of the invention
TABLE 10 Synthesis of the principal starting materials and reagents for the preparation of the present invention, Lifetid (Compound E)
The preparation method comprises the following steps:
A. adding 15.2g of compound C, 14.8g of HATU and 152mL of THF into a 500mL triangular flask, starting stirring, and cooling to 0-10 ℃ in an ice-water bath;
B. after stirring uniformly, keeping the temperature at 0-10 ℃, dropwise adding 20.2g of DIPEA, after completely dropwise adding, naturally returning the temperature to 20-30 ℃ for reaction for 15 +/-2 h, and after the reaction is controlled by HPLC, finishing the reaction when the content of the compound C is less than 0.1%, thus obtaining an intermediate compound;
C. 21.8g of Compound D, 41.4g K were added to a 1L beaker3PO4·7H2O and 150mL of pure water are stirred until the solid is completely dissolved to obtain a standby liquid for standby;
D. controlling the temperature to be 0-10 ℃, slowly dripping the standby liquid in the step C into the intermediate compound, completely dripping, naturally returning the temperature to 20-30 ℃ for reaction for 15 +/-2 hours, and performing HPLC (high performance liquid chromatography) controlled reaction until the intermediate compound is less than 0.1%, namely, the reaction is finished, thus obtaining a reaction liquid;
E. and (3) post-treatment: adjusting the pH of the reaction solution to 2-3 with 5N hydrochloric acid, separating the solution, extracting the lower aqueous phase with 60mL of ethyl acetate/tetrahydrofuran extract (EA: THF ═ 1:1) for 1 time, combining the organic phases, washing with 60mL of saturated saline solution for 1 time, concentrating under reduced pressure until the crude product is obtained, and directly concentrating the upper organic phase under reduced pressure until the crude product is obtained;
F. and (3) purifying a crude product: and (3) combining the crude products, dissolving the combined crude products in NaOH aqueous solution (2.7g of NaOH +300mL of pure water), filtering the obtained product with a filter membrane, adjusting the pH of the filtrate to 2-4 by using 5N hydrochloric acid, stirring the obtained product for crystallization for 2 +/-1 h, filtering the obtained product to obtain a product, and drying the product in a reduced pressure drying oven at the temperature of 50-60 ℃ until the weight of the product is constant to obtain 17.6g of a compound E (lifaste) which is a white solid and has the purity of 99.7% and the yield of.
The advantageous effects of the present invention are described below by way of test examples.
Test example 1 detection of Lifilsterobtained by the production method of the present invention
And taking the liffetiliast prepared by the method of example 2, and performing hydrogen spectrum and mass spectrum detection, and comparing with standard spectra of the liffetiliast in the literature.1The HNMR and MS spectra are shown in FIG. 1 and FIG. 2, respectively.
Example 2 preparation of liflstet1HNMR and MS mapping were resolved as follows:
MS:M+H＝615
1HNMR7.83(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 spectrum 1 and 2 obtained in the embodiment 2 of the invention are respectively consistent with the spectrum 3 and 4 of the liffetid document, so that the product obtained in the embodiment 2 is the liffetid.
For review, the synthesis route of the lifaste synthesis method is short, compared with the prior art, the reaction steps of protection and deprotection on functional groups are reduced, the chiral structure is introduced only in the last step, the configuration is kept unchanged in the reaction, and the racemization risk of chiral carbon atoms in the reaction process is reduced; the reaction condition is mild, the types of solvents and side reactions are less, and heavy metals such as palladium and the like are not used as catalysts in the synthesis process, so that the method is green and 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 (10)
1. A method for synthesizing lifustt, which is characterized in that: the method comprises the following steps:
step 1: uniformly stirring the compound A and the compound B in a solvent, adding DIPEA for reaction, and purifying reaction liquid obtained by the reaction to obtain a compound C;
step 2: uniformly stirring the compound C and HATU in a solvent, adding DIPEA for reaction, and obtaining an intermediate state after the reaction is finished;
and step 3: dissolving the compound D and soluble phosphate in pure water to obtain a standby solution; and adding the solution to be used into the intermediate state for reaction, and purifying the reaction solution obtained by the reaction to obtain the catalyst.
2. The method of synthesis according to claim 1, characterized in that: 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-to-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, the compound D, HATU, DIPEA and soluble phosphate is 1: 1-2: 1-4: 2-5; the weight-to-volume ratio of the compound C to the solvent is 1: 5-20 (w/v); the weight-to-volume ratio of the compound D to pure water is 1: 5-15 (w/v).
3. The method of synthesis according to claim 2, characterized in that: 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 the compound C, the compound D, HATU, DIPEA and soluble phosphate is 1:1.5:1:1.5: 3; the weight to 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).
4. The method of synthesis according to claim 1, characterized in that: 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.
5. The method of synthesis according to claim 1, characterized in that:
in the step 1, the DIPEA is slowly added dropwise; the temperature of the whole process in the step 1 is 0-10 ℃; the reaction time is 1-3 h; after the pH value is adjusted to 1-4 by strong acid, cooling and crystallizing, filtering, washing a filter cake, and drying under reduced pressure; wherein the strong acid is sulfuric acid or hydrochloric acid.
6. The method of synthesis according to claim 5, characterized in that:
in the step 1, the temperature of the whole process of the step 1 is 5 ℃; the reaction time is 2 h; the purification is that pH is adjusted to 3 by strong acid, the temperature is reduced to 0-10 ℃ for crystallization, the filtration is carried out, a filter cake is washed once by purified water and tetrahydrofuran respectively, and the decompression drying is carried out for 1-3 h at 50-60 ℃; wherein the strong acid is hydrochloric acid.
7. The method of synthesis according to claim 1, characterized in that:
in the step 2, the DIPEA is slowly added dropwise; the stirring and DIPEA adding temperature is 0-10 ℃, and the reaction temperature after the dripping is 20-30 ℃; the reaction time is 15-30 h.
8. The method of synthesis according to claim 7, characterized in that:
in the step 2, the temperature for stirring and dripping DIPEA is 5 ℃, and the reaction temperature after dripping is 25 ℃; the reaction time is 20 h.
9. The method of synthesis according to claim 1, characterized in that:
in the step 3, the step of adding the standby liquid into the intermediate state is to slowly and dropwise add the standby liquid into the intermediate state; the temperature of the solution to be added is 0-10 ℃, and the reaction temperature after the dropwise addition is 20-30 ℃; the reaction time is 15-30 h; the purification comprises the steps of adjusting the pH value to 2-4 by using strong acid, separating liquid, extracting the lower-layer water phase, combining organic phases, washing, concentrating under reduced pressure to dryness to obtain a crude product, directly concentrating the upper-layer organic phase under reduced pressure to dryness to obtain a crude product, dissolving the combined crude product, filtering, adjusting the pH value to 2-4 by using strong acid, stirring for crystallization 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 using a mixed solution of ethyl acetate and tetrahydrofuran, and the volume ratio of the ethyl acetate to the tetrahydrofuran is 1: 1-2.
10. The method of synthesis according to claim 9, characterized in that:
in the step 3, the temperature of the dropwise adding liquid to be used is 5 ℃, and the reaction temperature after the dropwise adding is 25 ℃; the reaction time is 20 h; after the pH value of the purified solution is adjusted to 3 by strong acid, separating the solution, extracting the lower aqueous phase, combining the organic phases, washing by saturated saline solution, concentrating under reduced pressure to dryness to obtain a crude product, directly concentrating the upper organic phase under reduced pressure to dryness to obtain a crude product, dissolving the combined crude product, filtering, adjusting the pH value to 3 by strong acid, stirring for crystallization for 2 hours, filtering to obtain a solid, and drying under reduced pressure at 50-60 ℃ to constant weight;
wherein the strong acid is hydrochloric acid; the extraction is the extraction of a mixed solution of ethyl acetate and tetrahydrofuran, and the volume ratio of the ethyl acetate to the tetrahydrofuran is 1:1.
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| CN112300139A (en) * | 2020-12-29 | 2021-02-02 | 南京佰麦生物技术有限公司 | Crystalline form of sitagliptin hydrate and preparation method thereof |
| CN113072471A (en) * | 2021-03-02 | 2021-07-06 | 四川美大康华康药业有限公司 | Lifeiste intermediate and preparation method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1902195A (en) * | 2003-11-05 | 2007-01-24 | 苏内西斯制药公司 | Modulators of cellular adhesion |
| 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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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1902195A (en) * | 2003-11-05 | 2007-01-24 | 苏内西斯制药公司 | Modulators of cellular adhesion |
| 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 |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112300139A (en) * | 2020-12-29 | 2021-02-02 | 南京佰麦生物技术有限公司 | Crystalline form of sitagliptin hydrate and preparation method thereof |
| CN113072471A (en) * | 2021-03-02 | 2021-07-06 | 四川美大康华康药业有限公司 | Lifeiste intermediate and preparation method thereof |
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