CN117362279A - PAR-1 inhibitor, chiral synthesis method thereof, preparation method and application of salt crystal form thereof - Google Patents
PAR-1 inhibitor, chiral synthesis method thereof, preparation method and application of salt crystal form thereof Download PDFInfo
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- CN117362279A CN117362279A CN202311674377.0A CN202311674377A CN117362279A CN 117362279 A CN117362279 A CN 117362279A CN 202311674377 A CN202311674377 A CN 202311674377A CN 117362279 A CN117362279 A CN 117362279A
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- 238000006735 epoxidation reaction Methods 0.000 description 1
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- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000006462 rearrangement reaction Methods 0.000 description 1
- 229940096995 sclareolide Drugs 0.000 description 1
- 239000013582 standard series solution Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- MLKXDPUZXIRXEP-MFOYZWKCSA-N sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 description 1
- 229960000894 sulindac Drugs 0.000 description 1
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- 238000004885 tandem mass spectrometry Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 239000003856 thrombin receptor antagonist Substances 0.000 description 1
- 229960000103 thrombolytic agent Drugs 0.000 description 1
- 230000002537 thrombolytic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- ZBGXUVOIWDMMJE-QHNZEKIYSA-N vorapaxar Chemical compound C(/[C@@H]1[C@H]2[C@H](C(O[C@@H]2C)=O)C[C@H]2[C@H]1CC[C@H](C2)NC(=O)OCC)=C\C(N=C1)=CC=C1C1=CC=CC(F)=C1 ZBGXUVOIWDMMJE-QHNZEKIYSA-N 0.000 description 1
- 229960005044 vorapaxar 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- 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
- C07B2200/13—Crystalline forms, e.g. polymorphs
-
- 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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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of pharmaceutical chemical industry, and particularly relates to a PAR-1 inhibitor, a chiral synthesis method thereof, a preparation method of salt crystal forms thereof and application of the salt crystal forms. The structural formula of the PAR-1 inhibitor is shown as follows:the PAR-1 inhibitor salt is prepared by five steps, then is dissolved in a solvent, added with an acid solution, cooled and crystallized to obtain the PAR-1 inhibitor salt crystal form. The PAR-1 inhibitor provided by the invention has the characteristics of definite target point, clear action mechanism, novel structure, high safety and high activity, and the chiral synthesis method of the PAR-1 inhibitor is used for obtaining the configuration overturning compound; the book is provided withThe invention also provides a preparation method of the sulfate crystal form of the PAR-1 inhibitor, the prepared crystal form is stable, and the PAR-1 inhibitor prepared by the invention has high value when being applied to treating thrombotic diseases.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemical industry, and particularly relates to a PAR-1 inhibitor, a chiral synthesis method thereof, a preparation method of salt crystal forms thereof and application of the salt crystal forms.
Background
Thrombosis, i.e. local blood clot formation. Among them, arterial thrombosis may lead to, for example, myocardial infarction, stroke, acute coronary syndrome, peripheral arterial disease, and the like; venous thrombosis can cause pulmonary embolism. Arteriovenous thrombosis is one of the leading causes of morbidity and mortality in cardiovascular disease, and at the same time, it is also one of the leading causes of mortality in cancer patients. Antithrombotic agents include anticoagulants, antiplatelet aggregation agents and thrombolytics. However, of these three different types of action, only the anticoagulant and antiplatelet aggregation drug effects are also possible. The shortcomings of the existing anticoagulants and the strong market opportunities will drive the development of the anticoagulants. And those having therapeutic effects at least equivalent to those of the existing anticoagulants, novel anticoagulants which are better in safety (particularly in reducing bleeding risk) and convenient to use (for oral administration, particularly for long-term use) are urgently needed.
Thrombin receptors (PARs) are one of G protein-coupled receptors (GPCRs), and the current PAR-1 class inhibition drugs have better anticoagulation activity, but have side effects of bleeding with different degrees in long-term clinical application, and the effective half-life of the drug is as long as 3-4 days and the terminal clearance half-life is as long as 8 days. Stopping the drug for a short time has poor effect on treating hemorrhage, and the effect lasts for at least 4 weeks after stopping the drug. Currently, there is no suitable therapeutic approach to combat the antiplatelet effects of this drug.
CN105732595A and CN115043820a both disclose a PAR-1 inhibitor having the general structural formula:the compound (II) in CN105732595A is prepared by taking andrographolide as a starting material, carrying out dehydration rearrangement reaction with aluminum oxide to obtain a compound (IV), carrying out epoxidation reaction with m-CPBA, carrying out acetalation reaction with 2, 2-dimethoxypropane, carrying out reaction with ozone to obtain a compound (II), and carrying out the reaction between the compound (II) and ozoneThe PAR-1 inhibitor is prepared by reacting the compound (III). CN115043820a also uses andrographolide as a raw material, and further optimizes the structure of the sulindac. CN110627710A and CN112759548A disclose a novel PAR-1 inhibitor of the formula +.>(I) The compound (I) is prepared by taking sclareolide as a starting material.
Although PAR-1 inhibitors are prepared in the above way, the drugs are not tightly combined with the target, the drug effect is poor, the pharmacokinetic parameters are poor, and the drug formation is poor, so that the problems of quick metabolism in vivo and adverse to patent medicine still exist.
Disclosure of Invention
The technical problem to be solved by the invention is to overcome the defects in the prior art, and provide the PAR-1 inhibitor which has the characteristics of definite target point, clear action mechanism, novel structure, high safety and high activity, and the chiral synthesis method of the PAR-1 inhibitor is used for obtaining the configuration overturning compound; the invention also provides a preparation method of the salt crystal form of the PAR-1 inhibitor, the prepared crystal form is stable, and the PAR-1 inhibitor prepared by the preparation method is applied to treatment of thrombotic diseases and has high value.
The structural formula of the PAR-1 inhibitor is shown as follows:
。
the preparation method of the PAR-1 inhibitor comprises the following steps:
(1) Andrographolide is used as a starting material, and an intermediate II is prepared by reaction, wherein the structural formula of the intermediate II is shown as follows:;
(2) Chiral selective reductive amination is carried out on carbonyl of the intermediate II, and simultaneously, the methyl configuration at the ortho position is reconstructed to prepare a compound III, wherein the structural formula of the compound III is shown as follows:
;
(3) The amino in the compound III is modified by ethyl chloroformate to prepare a compound IV, and the structural formula of the compound IV is shown as follows:;
(4) The compound IV is hydrolyzed and transesterified under the action of acid catalysis to prepare a compound V, and the structural formula of the compound V is shown as follows:;
(5) Under the action of lithium diisopropylamide, performing wittig reaction on a compound V and a compound VI to prepare a PAR-1 inhibitor; the structural formula of the compound VI is shown as follows:
。
the catalyst used in the chiral selective reductive amination in the step (2) is Ru ((R) -BINAP) (OAc) 2、 Ru((S)-BINAP)(OAc) 2 、Ru((S)-Segphos)(OAc) 2 Preferably Ru (S) -Segphos) (OAc) 2 。
The preparation method of the PAR-1 inhibitor salt crystal form comprises the following steps: dissolving the PAR-1 inhibitor in a solvent, adding an acid solution, stirring uniformly, cooling, crystallizing, filtering or centrifuging, and drying the obtained solid to obtain the PAR-1 inhibitor salt crystal form.
The acid solution is one of hydrochloric acid, sulfuric acid, phosphoric acid, fumaric acid and tartaric acid, and is preferably sulfuric acid.
Cooling to-20 deg.c for crystallization, preferably 0-10 deg.c.
The solvent is one of ethanol, methanol and acetonitrile, and the addition amount of the solvent is 5-100 times of the volume of the PAR-1 inhibitor, preferably 10-20 times of the volume.
The PAR-1 inhibitor salt crystal forms prepared by the preparation method have the application that: the medicine for treating thrombotic diseases can be orally taken.
Specifically, the preparation method of the PAR-1 inhibitor salt crystal form comprises the following steps:
(1) Andrographolide is used as a starting material, and an intermediate II is prepared through multi-step reaction, wherein the structural formula of the intermediate II is shown as follows:。
(2) Adding intermediate II into a reaction bottle, adding Trifluoroethanol (TFE) for dissolution, and sequentially adding ammonium acetate (NH) 4 OAc), chiral catalyst, communicating hydrogen steel bottle, ventilating 3 times, stirring at 80 deg.C for 10h, filtering to remove catalyst powder in reaction system, washing with ethyl acetate, vacuum distilling at 35 deg.C and less than or equal to-0.08 MPa to remove solvent to obtain crude product of compound III, and concentratingThe structure is as follows:
。
(3) Dissolving a crude product of the compound III with dichloromethane, transferring the solution into a round bottom flask, adding ethyl chloroformate, slowly adding Triethylamine (TEA) under stirring at 0 ℃, after the addition, stirring for 2 hours at room temperature, adding water, stirring for 5 minutes, transferring the system into a separating funnel, standing for layering, discharging a lower organic phase, adding dichloromethane into an upper water phase for extraction, removing the water phase, combining the organic phases, washing the organic phases with water, transferring the organic phases into a conical flask, drying the organic phases with anhydrous sodium sulfate, finishing drying, carrying out suction filtration, carrying out reduced pressure distillation, and separating and purifying the crude product by using column chromatography to obtain a white solid compound, namely a compound IV, wherein the structural formula of the compound IV is shown as follows:。
(4) Adding the compound IV into a reaction bottle, adding p-toluenesulfonic acid, adding acetone and water, heating and stirring for 4 hours at 80 ℃, adding saturated sodium bicarbonate solution, stirring for 5 minutes after the reaction is completed, transferring into a separating funnel, adding ethyl acetate, shaking uniformly, standing for layering, discharging an upper organic phase, drying by anhydrous sodium sulfate, drying, filtering, distilling under reduced pressure, and separating and purifying a crude product by column chromatography to obtain a white solid compound, namely a compound V, wherein the structural formula of the compound V is shown as follows:。
(5) Adding the compound V into a reaction bottle, adding tetrahydrofuran for dissolution, stirring for 5min at minus 20 ℃, slowly dripping lithium diisopropylamide, reacting for 1h after the addition, adding the compound VI, stirring for 2h at 0 ℃, adding a saturated ammonium chloride aqueous solution, stirring for 5min, transferring to a separating funnel, shaking uniformly, standing for layering, discharging an upper organic phase, adding Ethyl Acrylate (EA) into a lower water phase for extraction, discarding the water phase after the extraction is completed, merging the organic phases, drying with anhydrous sodium sulfate, carrying out suction filtration, distilling under reduced pressure, and refining the crude product with absolute ethyl alcohol to obtain a white solid compound, namely a PAR-1 inhibitor; the reaction process is as follows:
。
(6) Dissolving PAR-1 inhibitor in 5-100 times volume of solvent, adding acid solution, stirring, cooling to-20deg.C for crystallization, vacuum filtering or centrifuging, and oven drying the obtained solid to obtain alpha crystal form of PAR-1 inhibitor salt.
Compared with the prior art, the invention has the following beneficial effects:
(1) The alpha crystal form of the PAR-1 inhibitor salt prepared by the invention has good stability, is suitable for long-term storage, and effectively avoids crystal transformation in the processes of drug storage and development, thereby avoiding the change of bioavailability and drug effect.
(2) The preparation method of the PAR-1 inhibitor salt crystal form has the advantages of simple process, low cost and good repeatability, and the adopted solvent is nontoxic and has important value for the application and development of the medicine.
Drawings
FIG. 1 is a nuclear magnetic resonance spectrum of the compound IV prepared in example 1.
FIG. 2 is a mass spectrum of compound IV prepared in example 1.
FIG. 3 is a nuclear magnetic resonance spectrum of compound V prepared in example 1.
FIG. 4 is a mass spectrum of compound V prepared in example 1.
FIG. 5 is a nuclear magnetic resonance spectrum of the PAR-1 compound prepared in example 1.
FIG. 6 is a mass spectrum of the PAR-1 compound prepared in example 1.
FIG. 7 is an XRPD pattern for the crystalline form of the PAR-1 inhibitor salt prepared in example 2.
FIG. 8 is a single crystal structure of the PAR-1 inhibitor salt form prepared in example 2.
FIG. 9 is a graph of average blood concentration versus time in SD rats for PAR-1 inhibitors as tested on samples of PAR-1 inhibitor salts prepared in example 2.
Detailed Description
The invention will be further illustrated with reference to specific examples.
The raw materials used in the following examples and comparative examples are commercially available products.
Example 1
The preparation method of the PAR-1 inhibitor comprises the following steps:
(1) Andrographolide is used as a starting material to prepare an intermediate II through reaction, and specific preparation steps of the intermediate II are described in the section [ 0095-0114 ] of the specification in the example 1 of the Chinese patent CN115043820A published by 2022, 9 and 13.
(2) 10g of intermediate II was placed in a reaction flask, 50mL of Trifluoroethanol (TFE) was added to dissolve, and 4.78g of ammonium acetate (NH) 4 OAc), 2.49g chiral catalyst Ru (OAc) 2 [(R)-binap]And (3) connecting a hydrogen steel bottle, ventilating for 3 times, stirring at 80 ℃ for 10 hours, performing suction filtration to remove catalyst powder in a reaction system, washing with 40mL of ethyl acetate, and performing reduced pressure distillation to remove a solvent at 35 ℃ and less than or equal to-0.08 MPa to obtain a crude product of the compound III.
(3) Dissolving the crude product of the compound III with 100mL of dichloromethane, transferring the solution into a round bottom flask, adding 16.8g of ethyl chloroformate, slowly adding 31.4g of Triethylamine (TEA) under stirring at 0 ℃, stirring at room temperature for 2h after the addition, adding 100mL of water, stirring for 5min, transferring the system into a separating funnel after the stirring is completed, standing for layering, discharging a lower organic phase, adding 100mL of dichloromethane into an upper aqueous phase for extraction, removing the aqueous phase after the extraction is completed, merging the organic phases, washing the organic phase with 100mL of water, transferring the organic phase into a conical flask, drying the organic phase, filtering with suction, distilling under reduced pressure, separating and purifying the crude product by using column chromatography to obtain 7.9g of white solid compound, namely the compound IV, wherein the yield is 64.44%, and a nuclear magnetic diagram of the compound IV is shown in a graph shown in a figure 1 and a mass spectrum of the compound IV is shown in a figure 2.
(4) 7.00g of compound IV is added into a reaction bottle, 4.0g of p-toluenesulfonic acid is added, 20mL of acetone and 2mL of water are added, heating and stirring are carried out for 4 hours at 80 ℃, after the reaction is completed, 20mL of saturated sodium bicarbonate solution is added, stirring is carried out for 5 minutes, the mixture is transferred into a separating funnel, 20mL of ethyl acetate is added, shaking is carried out uniformly, standing and layering are carried out, an upper organic phase is discharged, anhydrous sodium sulfate is dried, drying is finished, suction filtration and reduced pressure distillation are carried out, and the crude product is separated and purified by column chromatography, thus obtaining 4.85g of white solid compound, namely compound V, the yield is 81.65%, the nuclear magnetic diagram of the compound V is shown in figure 3, and the mass spectrum is shown in figure 4.
(5) Adding 4.00g of compound V into a 50mL reaction bottle, adding 10mL of tetrahydrofuran for dissolution, stirring for 5min at-20 ℃, slowly dropwise adding 2.4mL of lithium diisopropylamide, after the addition is completed, reacting for 1h, adding 4.60g of compound VI, stirring for 2h at 0 ℃, completing the reaction, adding 15mL of saturated ammonium chloride aqueous solution, stirring for 5min, transferring into a separating funnel, shaking uniformly, standing for layering, discharging an upper organic phase, adding 15mL of Ethyl Acrylate (EA) into a lower aqueous phase, extracting, completing the extraction, discarding the aqueous phase, merging the organic phases, drying by anhydrous sodium sulfate, filtering, distilling under reduced pressure, and refining the crude product by absolute ethyl alcohol to obtain 5.02g of white solid compound, namely PAR-1 inhibitor, with the yield of 83.67%. The nuclear magnetic pattern of PAR-1 compound is shown in FIG. 5, and the mass spectrum is shown in FIG. 6.
Example 2
The preparation method of the PAR-1 inhibitor salt crystal form comprises the following steps:
dissolving 4.00g of PAR-1 inhibitor prepared in example 1 in 40mL of ethanol, namely dissolving 1.00g of concentrated sulfuric acid in 20mL of ethanol, adding the solution into the ethanol solution of the PAR-1 inhibitor, uniformly stirring, cooling to 5 ℃ for crystallization, stirring for 5h, suction filtering, and drying the obtained solid to obtain the alpha crystal form of the PAR-1 inhibitor sulfate.
XRPD (X-ray powder diffraction) analysis was performed on the alpha crystalline form of the PAR-1 inhibitor salt prepared in example 2 above, using a Bruker D8 facility X-ray powder diffractometer as shown in fig. 7, with characteristic peaks at 2θ values of 4.5 ° ± 0.2 °, 9.0 ° ± 0.2 °, 14.5 ° ± 0.2 °, 14.8 ° ± 0.2 °, 15.4 ° ± 0.2 °, 15.6 ° ± 0.2 °, 18.2 ° ± 0.2 °, 18.4 ° ± 0.2 °, 19.8 ° ± 0.2 °.
And for the analysis of the single crystal structure of example 2, the single crystal structure diagram is shown in FIG. 8, and the instrument brand is adopted: bruke, germany, model: d8 VENTURE, detection method: x-ray working voltage 50kV, working current 50mA, maximumThe 2 theta value is 68.395 degrees, the temperature is 248K, the Bruker APEX-II CCD surface detector is used for collecting diffraction intensity data, cuK alpha radiation is 5948 total diffraction points, 5644 independent diffraction points (rint=0.0510), and the data integrity is 99.1%. The crystal is colorless transparent block, belongs to orthorhombic system, and has space group of P2 1 2 1 2 1 Unit cell parameters:a=6.9085(3)Å,b=12.1914(5)Å,c=38.7742(16)Å,α=90°,βunit cell volume =90°, γ=90°V=3265.7(2)Å 3 The number of molecules in the unit cell z=4, and there are 1 molecule in the independent region of the unit cell.
Example 3
The preparation method of the PAR-1 inhibitor comprises the following steps:
(1) Andrographolide is used as a starting material to prepare an intermediate II through reaction, and specific preparation steps of the intermediate II are described in the section [ 0095-0114 ] of the specification in the example 1 of the Chinese patent CN115043820A published by 2022, 9 and 13.
(2) 10g of intermediate II was placed in a reaction flask, 50mL of Trifluoroethanol (TFE) was added to dissolve, and 4.78g of ammonium acetate (NH) 4 OAc), 2.50g chiral catalyst Ru ((S) -BINAP) (OAc) 2 And (3) connecting a hydrogen steel bottle, ventilating for 3 times, stirring at 80 ℃ for 10 hours, performing suction filtration to remove catalyst powder in a reaction system, washing with 40mL of ethyl acetate, and performing reduced pressure distillation to remove a solvent at 35 ℃ and less than or equal to-0.08 MPa to obtain a crude product of the compound III.
(3) The crude product of the compound III is dissolved by using 100mL of dichloromethane and transferred into a round bottom flask, 16.8g of ethyl chloroformate is added, 31.4g of Triethylamine (TEA) is slowly added under stirring at 0 ℃, after the addition is finished, stirring is carried out for 2 hours at room temperature, 100mL of water is added, stirring is carried out for 5 minutes, the system is transferred into a separating funnel after stirring, standing and layering are carried out, the lower organic phase is discharged, the upper aqueous phase is extracted by adding 100mL of dichloromethane, the extraction is finished, the aqueous phase is discarded, the organic phase is combined, the organic phase is washed by adding 100mL of water, the mixture is transferred into a conical flask, the organic phase is dried, the mixture is dried, suction filtration and reduced pressure distillation are carried out, and the crude product is separated and purified by using column chromatography, so that 5.3g of white solid compound is obtained, namely the compound IV, the yield is 43.23%.
(4) 7.00g of compound IV is added into a reaction bottle, 4.0g of p-toluenesulfonic acid is added, 20mL of acetone and 2mL of water are added, heating and stirring are carried out for 4 hours at 80 ℃, after the reaction is completed, 20mL of saturated sodium bicarbonate solution is added, stirring is carried out for 5 minutes, the mixture is transferred into a separating funnel, 20mL of ethyl acetate is added for shaking, standing and layering are carried out, an upper organic phase is discharged, anhydrous sodium sulfate is dried, drying is finished, suction filtration and reduced pressure distillation are carried out, and 4.85g of white solid compound, namely compound V, is obtained after the crude product is separated and purified by column chromatography, and the yield is 81.02 percent.
(5) Adding 4.00g of compound V into a 50mL reaction bottle, adding 10mL of tetrahydrofuran for dissolution, stirring for 5min at-20 ℃, slowly dropwise adding 2.4mL of lithium diisopropylamide, after the addition is completed, reacting for 1h, adding 4.60g of compound VI, stirring for 2h at 0 ℃, completing the reaction, adding 15mL of saturated ammonium chloride aqueous solution, stirring for 5min, transferring into a separating funnel, shaking uniformly, standing for layering, discharging an upper organic phase, adding 15mL of Ethyl Acrylate (EA) into a lower aqueous phase, extracting, completing the extraction, discarding the aqueous phase, merging the organic phases, drying by anhydrous sodium sulfate, filtering, distilling under reduced pressure, and refining the crude product by absolute ethyl alcohol to obtain 5.02g of white solid compound, namely PAR-1 inhibitor, with the yield of 82.85%.
Example 4
The preparation method of the PAR-1 inhibitor comprises the following steps:
(1) Andrographolide is used as a starting material to prepare an intermediate II through reaction, and specific preparation steps of the intermediate II are described in the section [ 0095-0114 ] of the specification in the example 1 of the Chinese patent CN115043820A published by 2022, 9 and 13.
(2) 10g of intermediate II was placed in a reaction flask, 50mL of Trifluoroethanol (TFE) was added to dissolve, and 4.78g of ammonium acetate (NH) 4 OAc), 2.50g chiral catalyst Ru ((R) -BINAP) (OAc) 2 And (3) connecting a hydrogen steel bottle, ventilating for 3 times, stirring at 80 ℃ for 10 hours, performing suction filtration to remove catalyst powder in a reaction system, washing with 40mL of ethyl acetate, and performing reduced pressure distillation to remove a solvent at 35 ℃ and less than or equal to-0.08 MPa to obtain a crude product of the compound III.
(3) The crude product of the compound III is dissolved by using 100mL of dichloromethane and transferred into a round bottom flask, 16.8g of ethyl chloroformate is added, 31.4g of Triethylamine (TEA) is slowly added under stirring at 0 ℃, after the addition is finished, stirring is carried out for 2 hours at room temperature, 100mL of water is added, stirring is carried out for 5 minutes, the system is transferred into a separating funnel after stirring, standing and layering are carried out, the lower organic phase is discharged, the upper aqueous phase is extracted by adding 100mL of dichloromethane, the extraction is finished, the aqueous phase is discarded, the organic phase is combined, the organic phase is washed by adding 100mL of water, the mixture is transferred into a conical flask, the organic phase is dried, the mixture is dried, suction filtration and reduced pressure distillation are carried out, and the crude product is separated and purified by using column chromatography, so that 4.2g of white solid compound is obtained, namely the compound IV, and the yield is 34.26%.
(4) 7.00g of compound IV is added into a reaction bottle, 4.0g of p-toluenesulfonic acid is added, 20mL of acetone and 2mL of water are added, heating and stirring are carried out for 4 hours at 80 ℃, after the reaction is completed, 20mL of saturated sodium bicarbonate solution is added, stirring is carried out for 5 minutes, the mixture is transferred into a separating funnel, 20mL of ethyl acetate is added for shaking, standing and layering are carried out, an upper organic phase is discharged, anhydrous sodium sulfate is dried, drying is finished, suction filtration and reduced pressure distillation are carried out, and 4.85g of white solid compound, namely compound V, is obtained after the crude product is separated and purified by column chromatography, and the yield is 80.01 percent.
(5) Adding 4.00g of compound V into a 50mL reaction bottle, adding 10mL of tetrahydrofuran for dissolution, stirring for 5min at-20 ℃, slowly dropwise adding 2.4mL of lithium diisopropylamide, after the addition is completed, reacting for 1h, adding 4.60g of compound VI, stirring for 2h at 0 ℃, completing the reaction, adding 15mL of saturated ammonium chloride aqueous solution, stirring for 5min, transferring into a separating funnel, shaking uniformly, standing for layering, discharging an upper organic phase, adding 15mL of Ethyl Acrylate (EA) into a lower aqueous phase, extracting, completing the extraction, discarding the aqueous phase, merging the organic phases, drying by anhydrous sodium sulfate, filtering, distilling under reduced pressure, and refining the crude product by absolute ethyl alcohol to obtain 5.02g of white solid compound, namely PAR-1 inhibitor, with the yield of 81.62%.
Example 5
The preparation method of the PAR-1 inhibitor salt crystal form comprises the following steps:
1.00g of PAR-1 inhibitor prepared in example 1 is dissolved in 100mL of acetonitrile, 0.50g of sulfuric acid is weighed to be dissolved by 20mL of acetonitrile, then the solution is added into the acetonitrile solution of the PAR-1 inhibitor, the mixture is stirred uniformly, the temperature is reduced to 20 ℃ for crystallization, the mixture is stirred for 5h, suction filtration is carried out, and the obtained solid is dried to obtain the alpha crystal form of the sulfate of the PAR-1 inhibitor.
Example 6
The preparation method of the PAR-1 inhibitor salt crystal form comprises the following steps:
1.00g of PAR-1 inhibitor prepared in example 1 is dissolved in 50mL of methanol, 0.50g of sulfuric acid is dissolved in 20mL of methanol, then the solution is added into the methanol solution of the PAR-1 inhibitor, the solution is stirred uniformly, the temperature is reduced to minus 20 ℃ for crystallization, the stirring crystallization is carried out for 5 hours, suction filtration is carried out, and the obtained solid is dried to obtain the alpha crystal form of the sulfate of the PAR-1 inhibitor.
The PAR-1 inhibitors prepared in example 1 above were subjected to bioavailability assays.
(1) Biological sample collection
8 SD rats (male) were randomly divided into 2 groups of 4. All animals were fasted for 12h, weighed, dosed with PAR-1 inhibitor, each group was bled by rat jugular puncture for 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h and 24h before and after dosing, each sample was collected at about 0.2mL whole blood/time point, placed in a ice box heparinizing centrifuge tube after the blood collection, and plasma was centrifuged within 1h (centrifugation conditions: 2-8 ℃,8000rpm,10 min) and stored in a-80 ℃ refrigerator before analysis of the collected plasma.
(2) Sample testing
Chromatographic conditions: chromatographic column: accucore C18 (2.1×50mm,2.6 μm), mobile phase: 0.1wt.% formic acid aqueous solution (a): 0.2wt.% acetonitrile formate (B), gradient elution, column temperature: 40 ℃, sample injection volume: 5 μl as shown in table 1.
TABLE 1 gradient elution conditions
Mass spectrometry conditions: AB SCIEX 5500 triple quadrupole tandem mass spectrometry system, wherein the ion source is ESI source, CUR:35psi, CAD:8psi, IS:5500psi, TEM:550 ℃, gas1:55psi, gas2:50psi, MRM mode. The detection conditions are shown in table 2,
TABLE 2 detection conditions
Sample processing: 40 [ mu ] L of plasma sample is taken and placed in a 1.5mL centrifuge tube, 160 [ mu ] L of acetonitrile solution (TBTM 100 ng/mL) is added, vortex 2min and 13000rpm (8 ℃) are centrifuged for 6min, and supernatant sample injection 5 [ mu ] L is taken for detection.
Sample analysis: taking blank SD rat plasma, sequentially adding PAR-1 inhibitor standard series solution, and preparing a standard sample. The concentration of the object to be measured is taken as an abscissa, the peak area ratio of the object to be measured to the internal standard is taken as an ordinate, and a weighted least square method (weight is 1/x 2 ) The linear regression equation obtained by carrying out regression operation is a standard curve, the standard curve is Y=0.00277X+0.0000757, the regression coefficient r=0.9949, the sample concentration is analyzed according to the standard curve, meanwhile, the prepared follow-up quality control samples are uniformly distributed in the middle of the sample to be detected, the deviation of the measurement result of the quality control samples is less than 15%, and the result of 1/3 quality control samples is allowed to be out of limit at most but cannot appear in the same concentration.
(3) Statistical analysis
Calculating PAR-1 inhibitor t according to blood concentration data by adopting Phoenix WinNonlin 8.1.8.1 software non-atrioventricular model 1/2 、Vd、CL、AUC、C max 、T max Pharmacokinetic parameters such as MRT. At the same time according to AUC (0-t) Bioavailability of PAR-1 inhibitor oral route was calculated, f=auc (i.g.)/(10×auc (i.v.)) ×100%.
(4) Blood concentration-time data
The results of measuring PAR-1 inhibitor concentration in plasma at different times after gastric lavage and intravenous administration of PAR-1 inhibitor to SD rats are shown in Table 3, and a graph of average blood concentration of PAR-1 inhibitor in SD rats versus time is shown in FIG. 9, wherein A represents average blood concentration of PAR-1 inhibitor in SD rats versus time at an administration concentration of 1mg/kg, and B represents average blood concentration of PAR-1 inhibitor in SD rats versus time at an administration concentration of 10 mg/kg.
TABLE 3 average plasma concentration versus time data for PAR-1 inhibitors in SD rats
(5) Pharmacokinetic parameters and bioavailability
After the SD rats were lavaged and the PAR-1 inhibitor was intravenously administered, pharmacokinetic parameters were calculated using a Phoenix WinNonlin 8.1.1 software non-compartmental model, and the average pharmacokinetic parameters are shown in Table 4, wherein the administration concentration (10 mg/kg) was data after the SD rats were lavaged and the administration concentration (1 mg/kg) was data after the SD rats were intravenously administered the PAR-1 inhibitor.
TABLE 4PAR-1 inhibitors PK parameters in SD rats
(6) Conclusion(s)
As can be seen from Table 4, after intravenous administration of 1mg/kg of PAR-1 inhibitor to rats, the Cmax of PAR-1 inhibitor in blood plasma was 829.58.+ -. 48.70ng/mL, AUC (0-t) 1716.23.+ -. 224.74 ng/(mL. Times.h), AUC (0-. Infinity.) is 1755.40.+ -. 246.10 ng/(mL. Times.h) (n=4).
As can be seen from Table 4, after 10mg/kg of PAR-1 inhibitor was administered to rats by lavage, the Cmax of PAR-1 inhibitor in blood plasma was 1127.57.+ -. 133.59ng/mL, AUC (0-t) 9631.51.+ -. 1629.03 ng/(mL. Times.h), AUC (0-. Infinity.) is 10692.83.+ -. 2608.94 ng/(mL. Times.h) (n=4). According to AUC (0-t) The bioavailability of the PAR-1 inhibitor after intragastric administration was calculated to be 56.12%.
The bioavailability of the commercial co-target drug Volappaxa for rats is 33% (Discovery of a Novel, orally Active Himbacine-Based Thrombin Receptor Antagonist (SCH 530348) with Potent Antiplatelet Activity.J. Med. Chem. 2008, 51, 3061-3064.) whereas the bioavailability of the PAR-1 inhibitor prepared by the invention is 56.12%, which has obvious advantages.
Claims (8)
1. A PAR-1 inhibitor characterized by: the structural formula is as follows:
。
2. a process for the preparation of a PAR-1 inhibitor as claimed in claim 1, characterized in that: the method comprises the following steps:
(1) Andrographolide is used as a starting material, and an intermediate II is prepared by reaction, wherein the structural formula of the intermediate II is shown as follows:;
(2) Chiral selective reductive amination is carried out on carbonyl of the intermediate II, and simultaneously, the methyl configuration at the ortho position is reconstructed to prepare a compound III, wherein the structural formula of the compound III is shown as follows:;
(3) The amino in the compound III is modified by ethyl chloroformate to prepare a compound IV, and the structural formula of the compound IV is shown as follows:;
(4) The compound IV is hydrolyzed and transesterified under the action of acid catalysis to prepare a compound V, and the structural formula of the compound V is shown as follows:;
(5) Under the action of lithium diisopropylamide, performing wittig reaction on a compound V and a compound VI to prepare a PAR-1 inhibitor; the structural formula of the compound VI is shown as follows:。
3. the method for producing a PAR-1 inhibitor according to claim 2, which comprisesIs characterized in that: the catalyst used in the chiral selective reductive amination in the step (2) is Ru ((R) -BINAP) (OAc) 2、 Ru((S)-BINAP)(OAc) 2 、Ru((S)-Segphos)(OAc) 2 One of them.
4. A process for the preparation of the crystalline form of the PAR-1 inhibitor salt of claim 1, characterized by: the method comprises the following steps: dissolving the PAR-1 inhibitor in a solvent, adding an acid solution, stirring uniformly, cooling, crystallizing, filtering or centrifuging, and drying the obtained solid to obtain the PAR-1 inhibitor salt crystal form.
5. The process for preparing a crystalline form of a PAR-1 inhibitor salt according to claim 4, wherein: the acid solution is one of hydrochloric acid, sulfuric acid, phosphoric acid, fumaric acid and tartaric acid.
6. The process for preparing a crystalline form of a PAR-1 inhibitor salt according to claim 4, wherein: cooling to-20 deg.c for crystallization.
7. The process for preparing a crystalline form of a PAR-1 inhibitor salt according to claim 4, wherein: the solvent is one of ethanol, methanol and acetonitrile, and the addition amount of the solvent is 5-100 times of the volume of the PAR-1 inhibitor.
8. Use of the PAR-1 inhibitor salt form prepared by the process for preparing the PAR-1 inhibitor salt form of any one of claims 4 to 7, characterized in that: a medicament for treating thrombotic diseases.
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CHRISTOPHER K. HILL ET AL: "Site-selective oxidation, amination and epimerization reactions of complex polyols enabled by transfer hydrogenation", NATURE CHEMISTRY, pages 1 - 9 * |
M.S.I. ELALAMI ET AL.: "Synthesis of chiral bifunctional ligands based on a-pinene and their use in ruthenium catalyzed asymmetric transfer hydrogenation", C. R. CHIMIE, vol. 12, pages 1253 - 1258 * |
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