CN116730936A - Preparation method of small molecule for promoting interaction of FXR protein and Caspase8 protein - Google Patents
Preparation method of small molecule for promoting interaction of FXR protein and Caspase8 protein Download PDFInfo
- Publication number
- CN116730936A CN116730936A CN202310677135.0A CN202310677135A CN116730936A CN 116730936 A CN116730936 A CN 116730936A CN 202310677135 A CN202310677135 A CN 202310677135A CN 116730936 A CN116730936 A CN 116730936A
- Authority
- CN
- China
- Prior art keywords
- compound
- protein
- preparation
- small molecule
- organic solvent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- 150000003384 small molecules Chemical class 0.000 title claims abstract description 22
- 102000004091 Caspase-8 Human genes 0.000 title claims abstract description 21
- 108090000538 Caspase-8 Proteins 0.000 title claims abstract description 21
- 102100038495 Bile acid receptor Human genes 0.000 title claims abstract description 19
- 101000603876 Homo sapiens Bile acid receptor Proteins 0.000 title claims abstract description 19
- 230000003993 interaction Effects 0.000 title claims abstract description 15
- 230000001737 promoting effect Effects 0.000 title claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 11
- 239000003153 chemical reaction reagent Substances 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 9
- 229940126214 compound 3 Drugs 0.000 claims description 8
- 239000007821 HATU Substances 0.000 claims description 7
- 229940125904 compound 1 Drugs 0.000 claims description 6
- 229940125782 compound 2 Drugs 0.000 claims description 6
- 229940125898 compound 5 Drugs 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 125000003158 alcohol group Chemical group 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 238000006798 ring closing metathesis reaction Methods 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 230000006909 anti-apoptosis Effects 0.000 abstract description 2
- 230000002300 anti-fibrosis Effects 0.000 abstract description 2
- 230000033228 biological regulation Effects 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- -1 Q1 Chemical compound 0.000 description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 230000006907 apoptotic process Effects 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000004440 column chromatography Methods 0.000 description 9
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 6
- 239000003623 enhancer Substances 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000012265 solid product Substances 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 description 4
- ACMJJQYSPUPMPN-UHFFFAOYSA-N 4-chloro-3-fluoroaniline Chemical compound NC1=CC=C(Cl)C(F)=C1 ACMJJQYSPUPMPN-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 3
- BRWIZMBXBAOCCF-UHFFFAOYSA-N hydrazinecarbothioamide Chemical compound NNC(N)=S BRWIZMBXBAOCCF-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 229940107700 pyruvic acid Drugs 0.000 description 3
- 238000002390 rotary evaporation Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 210000003494 hepatocyte Anatomy 0.000 description 2
- 208000019423 liver disease Diseases 0.000 description 2
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000012744 reinforcing agent Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- CRDAMVZIKSXKFV-FBXUGWQNSA-N (2-cis,6-cis)-farnesol Chemical compound CC(C)=CCC\C(C)=C/CC\C(C)=C/CO CRDAMVZIKSXKFV-FBXUGWQNSA-N 0.000 description 1
- 239000000260 (2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-ol Substances 0.000 description 1
- 102100026693 FAS-associated death domain protein Human genes 0.000 description 1
- 101000643956 Homo sapiens Cytochrome b-c1 complex subunit Rieske, mitochondrial Proteins 0.000 description 1
- 101000911074 Homo sapiens FAS-associated death domain protein Proteins 0.000 description 1
- 101001099199 Homo sapiens RalA-binding protein 1 Proteins 0.000 description 1
- 101001109145 Homo sapiens Receptor-interacting serine/threonine-protein kinase 1 Proteins 0.000 description 1
- 102100022501 Receptor-interacting serine/threonine-protein kinase 1 Human genes 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229940043259 farnesol Drugs 0.000 description 1
- 229930002886 farnesol Natural products 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 230000006882 induction of apoptosis Effects 0.000 description 1
- 102000027528 liver X receptor-like Human genes 0.000 description 1
- 108091008780 liver X receptor-like Proteins 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000006916 protein interaction Effects 0.000 description 1
- 230000004850 protein–protein interaction Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- CRDAMVZIKSXKFV-UHFFFAOYSA-N trans-Farnesol Natural products CC(C)=CCCC(C)=CCCC(C)=CCO CRDAMVZIKSXKFV-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
- C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
- C07D253/06—1,2,4-Triazines
- C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
- C07D253/07—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D253/075—Two hetero atoms, in positions 3 and 5
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Gastroenterology & Hepatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of a small molecule for promoting interaction of FXR protein and Caspase8 protein. The small molecule shown in the formula I can be synthesized by three steps. The preparation method of the small molecule provided by the invention has novel route and defines the initial raw material and the synthesis route, thereby obtaining the compound with high selection and high yield. The preparation method is simple, the post-treatment is simple and convenient, and the product can be obtained without extreme conditions. The small molecule prepared by the invention can be used for exploring the interaction regulation and control between FXR protein and Caspase8 protein; can be developed into anti-apoptosis or anti-fibrosis drugs.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and relates to a preparation method of a small molecule for promoting interaction of FXR protein and Caspase8 protein.
Background
Studies have shown that nonalcoholic steatohepatitis (Nonalcoholic steatohepatitis, NASH) is accompanied by significant apoptosis in liver fibrosis. The agonist of the farnesol X receptor (Farnesoid X Receptor, FXR, also called NR1H 4) has no improvement effect on the significantly-increased hepatic apoptosis state under the disease states of NASH and the like, and is one of the main reasons of clinical efficacy limitation. In addition, previous studies have shown that there is a stable protein-protein interaction between FXR protein and Caspase8 protein in hepatocytes. When hepatocytes are stimulated by apoptosis, the interaction between FXR and Caspase8 protein is reduced, so that Caspase8 and FADD, RIP1 are combined with each other to form an apoptotic complex, which promotes the shear activation of Caspase8 and promotes the progress of apoptosis. Thus, stabilizing and enhancing the interaction between FXR protein and Caspase8 protein is an important strategy to block apoptosis signaling and apoptosis development. However, how the interactions between FXR protein and Caspase8 protein are regulated is not known.
CN2021116814033 discloses the use of an enhancer 3C1 for the preparation of an enhancer for the interaction of FXR protein and Caspase8 protein. The structural formula of the reinforcing agent 3C1 is as follows:
the enhancer can promote interaction between FXR protein and Caspase8 protein, further inhibit recruitment of Caspase8 to apoptosis complex, block formation of apoptosis complex, inhibit shear activation of Caspase8, block apoptosis process, and inhibit apoptosis. Therefore, the enhancer can be used for preparing medicines for treating liver diseases with apoptosis phenotype.
At present, the enhancer is used as a small molecule with a simple structure, and the synthetic route of the enhancer is not clear.
Disclosure of Invention
The invention aims to: the invention aims to provide a preparation method of a small molecule for promoting interaction of FXR protein and Caspase8 protein. At present, the synthetic route of the small molecule is not clear, and the preparation method provided by the invention has clear starting materials and synthetic routes, so that the compound can be obtained with high selectivity and high yield, and the synthesis method is simple, the post-treatment is simple and convenient, and the product can be obtained without extreme conditions.
The technical scheme is as follows: the aim of the invention is achieved by the following technical scheme:
the invention provides a preparation method of a small molecule for promoting interaction of FXR protein and Caspase8 protein, which comprises the following synthetic route:
the small molecule has a structure shown in a formula I:
wherein,,
R 1 ，R 2 ，R 3 ，R 4 ，R 5 each independently selected from the group consisting of halogen or H,
the halogen is F, cl, br or I.
The invention also provides a preparation method of the small molecule, which comprises the following steps:
(1) Reacting the compound 1 with the compound 2 in the presence of weak base in an organic solvent to obtain a compound 3;
(2) Heating and refluxing the compound 3 and the Lawson reagent in an organic solvent to react to obtain a compound 4;
(3) Compound 4 reacts with compound 5 under acidic condition, and ring closure is carried out under weak alkaline condition, thus obtaining compound of formula I.
Preferably, in step (1), the weak base is selected from the group consisting of N, N-diisopropylethylamine.
Preferably, in step (1), the organic solvent is selected from the group consisting of N, N-dimethylformamide.
Preferably, in the step (1), after the compound 2 reacts with HATU for 10-60 min at the temperature of-5 ℃, the compound 1 and weak base are added for reaction at room temperature for 6-18 h; the molar ratio of the compound 1, the compound 2 and the HATU to the weak base is 1 (1.1-2.0): 1.3-3.0.
Preferably, in step (2), the organic solvent is selected from toluene.
Preferably, in the step (2), the compound 3 and the Lawsen reagent are reacted for 12 to 16 hours at a temperature of between 40 and 100 ℃; the mol ratio of the compound 3 to the Lawson reagent is (1.5-3.0): 0.8-1.2.
Preferably, in the step (3), the compound 4 and the compound 5 are dissolved in a mixed solvent, hydrochloric acid solution and acetic acid are added for reaction for 0.5 to 3 hours at 60 to 90 ℃, the solvent is distilled off, then an organic solvent is added, 10 percent NaOH solution is used for adjusting the pH value to be 8 to 9, and the reaction is carried out for 4 to 22 hours at 60 to 90 ℃; the molar ratio of the compound 4 to the compound 5 is (0.6-1.8): 1.
Further, the mixed solvent is alcohol and water, and the organic solvent is selected from ethanol.
The small molecule of the invention is selected from the following compounds:
the preparation method provided by the invention not only can synthesize small molecules Q1 (namely reinforcing agent 3C 1), but also can synthesize and obtain compounds Q2, Q3, Q4 and Q5. The preparation method of the compound Q2-Q5 is the same as that of the compound Q1, and the difference is that the initial raw materials are different in structure from the initial raw materials of the compound Q1, and the raw materials substituted by different halogens on benzene rings are selected for reaction, so that the compound Q2-Q5 can be obtained.
By adopting the preparation method provided by the invention, a class of small molecules for promoting the interaction of FXR protein and Caspase8 protein can be prepared, and the small molecules can be used for exploring the interaction regulation between FXR protein and Caspase8 protein; can be developed into anti-apoptosis or anti-fibrosis medicine with good curative effect and small toxic and side effects. All of these efforts will provide important support for the subsequent development of such small molecules.
The beneficial effects are that:
the preparation method of the small molecule provided by the invention has novel route, defines the starting materials and synthesis paths, has high selectivity of reaction sites, and causes fewer byproducts and higher yield, thereby obtaining the compound with high selectivity and high yield. The preparation method is simple, the post-treatment is simple and convenient, and the product can be obtained without extreme conditions. This is of great importance in facilitating the research of FXR protein interactions with Caspase8 proteins and the treatment of liver diseases.
Detailed Description
The technical scheme of the present invention is described in detail below through specific examples, but the scope of the present invention is not limited to the examples.
The experimental methods in the following examples are conventional methods unless otherwise specified. The test materials used in the examples described below, unless otherwise specified, are all commercially available products.
Example 1
(1) Preparation of N- (3-chloro-4-fluorophenyl) -2-oxopropanamide
Pyruvic acid (764. Mu.l, 11 mmol) was dissolved in N, N-dimethylformamide (15 ml), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (HATU, 4183mg,11 mmol) was added thereto and reacted at 0℃for 30 minutes, then 3-fluoro-4-chloroaniline (1456 mg,10 mmol), N, N-diisopropylethylamine (2612. Mu.l, 15 mmol) was added thereto and reacted at room temperature for 12 hours, the reaction mixture was diluted with ethyl acetate, water and extracted three times with ethyl acetate after the completion of the reaction, and the organic phases were combined, alternately washed 5 times with a 5% hydrochloric acid solution, a saturated NaCl solution, and anhydrous Na 2 SO 4 Dried, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate=8:1, v/v) to give a white solid product (1219 mg, yield 56.7%).
1 H NMR(300MHz,CDCl3)δ(ppm)8.76(s,1H),7.88(dd,J＝6.5,2.7Hz,1H),7.47(ddd,J＝8.9,4.1,2.7Hz,1H),7.16(t,J＝8.7Hz,1H),2.59(s,3H)。
ESI-MS(m/z)：214.0069[M+H - ]。
(2) Preparation of N- (3-chloro-4-fluorophenyl) -2-thiopropionamide
N- (3-chloro-4-fluorophenyl) -2-oxopropanamide (862 mg,4 mmol) was dissolved in 8ml toluene, to which was added the Lawson reagent (720 mg,2mmol, available from Ann Ji Chemie), reacted at 78℃for 14 hours, after completion of the reaction, concentrated, purified by column chromatography (petroleum ether: ethyl acetate=20:1, v/v) to give the product as a white solid (469 mg, yield 50.5%).
1 H NMR(300MHz,CDCl3)δ(ppm)10.53(s,1H),8.29(dd,J＝6.5,2.7Hz,1H),7.80(ddd,J＝9.0,4.1,2.7Hz,1H),7.32–7.14(m,1H),2.76(s,3H)。
ESI-MS(m/z)：299.9835[M+H - ]。
(3) Preparation of 5- ((3-chloro-4-fluorophenyl) amino) -6-methyl-1, 2, 4-triazine-3 (2H) -thione (Compound Q1)
N- (3-chloro-4-fluorophenyl) -2-thiopropionamide (231 mg,1 mmol), thiosemicarbazide (91 mg,1 mmol) was dissolved in 3ml ethanol: to a solution of water (1:1, v/v), acetic acid (0.2 ml) and 37% hydrochloric acid (0.02 ml) were added, and after the reaction was completed for 1 hour, the solvent was removed by rotary evaporation, filtration, washing the cake with water three times, dissolving the cake in 10ml of ethanol, adjusting ph=8 to 9 with 10% naoh solution, and reacting at 78 ℃ for 20 hours. After completion of the reaction, the mixture was concentrated and purified by column chromatography (dichloromethane: methanol=50:1, v/v) to give a white solid product (140 mg, yield 51.7%, purity 98.9%).
1 H NMR(300MHz,DMSO-d 6 )δ(ppm)13.66(s,1H),9.53(s,1H),8.04(dd,J＝6.8,2.6Hz,1H),7.75(ddd,J＝9.0,4.5,2.6Hz,1H),7.49(t,J＝9.1Hz,1H),2.33(s,3H)。
ESI-MS(m/z)：269.0069[M+H - ]。
Example 2
(1) Preparation of N- (3-chloro-4-fluorophenyl) -2-oxopropanamide
Dissolving pyruvic acid (1390. Mu.l, 20 mmol) in N, N-diTo methylformamide (30 ml), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (HATU, 7605mg,20 mmol) was added thereto, reacted at-5℃for 60 minutes, then 3-fluoro-4-chloroaniline (1456 mg,10 mmol), N, N-diisopropylethylamine (5224. Mu.l, 30 mmol) was added, reacted at room temperature for 18 hours, after completion of the reaction, the reaction solution was diluted with ethyl acetate and water, extracted three times with ethyl acetate, and the organic phase was combined, and 5% hydrochloric acid solution and saturated NaCl solution were alternately washed 5 times, anhydrous Na 2 SO 4 Dried, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate=8:1, v/v) to give a white solid product (982.5 mg, yield 45.7%).
(2) Preparation of N- (3-chloro-4-fluorophenyl) -2-thiopropionamide
N- (3-chloro-4-fluorophenyl) -2-oxopropanamide (647 mg,3 mmol) was dissolved in 8ml toluene, to which was added lawsen reagent (806 mg,2mmol, available from Anaglycone chemical) and reacted at 100℃for 12 hours, after the reaction was completed, concentrated and purified by column chromatography (petroleum ether: ethyl acetate=20:1, v/v) to give the product as a white solid (210 mg, yield 45.5%).
(3) Preparation of 5- ((3-chloro-4-fluorophenyl) amino) -6-methyl-1, 2, 4-triazine-3 (2H) -thione (Compound Q1)
N- (3-chloro-4-fluorophenyl) -2-thiopropionamide (92 mg,0.4 mmol), thiosemicarbazide (60 mg,0.66 mmol) was dissolved in 2ml ethanol: to a solution of water (1:1, v/v), acetic acid (132. Mu.l) and 37% hydrochloric acid (13.2. Mu.l) were added, and after completion of the reaction, the solvent was removed by rotary evaporation, filtration and washing the cake with water three times, the cake was dissolved in 10ml of ethanol, and pH=8 to 9 was adjusted with a 10% NaOH solution, and the reaction was carried out at 90℃for 4 hours. After completion of the reaction, the mixture was concentrated and purified by column chromatography (dichloromethane: methanol=50:1, v/v) to give a white solid product (48 mg, yield 44.5%, purity 90.1%).
Example 3
(1) Preparation of N- (3-chloro-4-fluorophenyl) -2-oxopropanamide
Pyruvic acid (1043. Mu.l, 15 mmol) was dissolved in N, N-dimethylformamide (20 ml), to which O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylurea hexafluorophosphate (HATU,5704mg,15 mmol) at 5℃for 10 min, then 3-fluoro-4-chloroaniline (1456 mg,10 mmol), N-diisopropylethylamine (3483. Mu.l, 20 mmol) were added, the reaction was allowed to proceed at room temperature for 6h, the reaction mixture was diluted with ethyl acetate, water, extracted three times with ethyl acetate, the organic phases were combined, 5% hydrochloric acid solution, saturated NaCl solution were alternately washed 5 times, anhydrous Na 2 SO 4 Dried, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate=8:1, v/v) to give a white solid product (10011 mg, yield 47.0%).
(2) Preparation of N- (3-chloro-4-fluorophenyl) -2-thiopropionamide
N- (3-chloro-4-fluorophenyl) -2-oxopropanamide (862mg, 4 mmol) was dissolved in 8ml toluene, to which was added lawsen reagent (1293 mg,3.2mmol, this reagent was purchased from Ann Ji Chemicals), reacted at 40℃for 16 hours, after the completion of the reaction, concentrated, purified by column chromatography (petroleum ether: ethyl acetate=20:1, v/v) to give the product as a white solid (237 mg, yield 32.1%).
(3) Preparation of 5- ((3-chloro-4-fluorophenyl) amino) -6-methyl-1, 2, 4-triazine-3 (2H) -thione (Compound Q1)
N- (3-chloro-4-fluorophenyl) -2-thiopropionamide (209 mg,0.9 mmol), thiosemicarbazide (46 mg,0.5 mmol) was dissolved in 3ml ethanol: to a solution of water (1:1, v/v), acetic acid (0.1 ml) and 37% hydrochloric acid (0.01 ml) were added, and after the completion of the reaction, the solvent was removed by rotary evaporation, and the filter cake was filtered, washed three times, dissolved in 10ml of ethanol, adjusted to ph=8 to 9 with 10% naoh solution, and reacted at 60 ℃ for 22 hours. After completion of the reaction, the mixture was concentrated and purified by column chromatography (dichloromethane: methanol=50:1, v/v) to give a white solid product (33 mg, yield 40.5%, purity 89.7%).
As described above, although the present invention has been shown and described with reference to certain preferred embodiments, it is not to be construed as limiting the invention itself. Various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (10)
1. A preparation method of a small molecule for promoting interaction of FXR protein and Caspase8 protein is characterized by comprising the following synthetic route:
the small molecule has a structure shown in a formula I:
wherein,,
R 1 ，R 2 ，R 3 ，R 4 ，R 5 each independently selected from the group consisting of halogen or H,
the halogen is F, cl, br or I.
2. The method of manufacturing according to claim 1, comprising the steps of:
(1) Reacting the compound 1 with the compound 2 in the presence of weak base in an organic solvent to obtain a compound 3;
(2) Heating and reacting the compound 3 with a Lawson reagent in an organic solvent to obtain a compound 4;
(3) Compound 4 reacts with compound 5 under acidic condition, and ring closure is carried out under weak alkaline condition, thus obtaining compound of formula I.
3. The process according to claim 2, wherein in step (1), the weak base is selected from the group consisting of N, N-diisopropylethylamine.
4. The method according to claim 2, wherein in step (1), the organic solvent is selected from the group consisting of N, N-dimethylformamide.
5. The preparation method according to claim 2, wherein in the step (1), after the reaction of the compound 2 with HATU at-5 to 5 ℃ for 10 to 60 minutes, the compound 1 and weak base are added and reacted at room temperature for 6 to 18 hours; the molar ratio of the compound 1, the compound 2 and the HATU to the weak base is 1 (1.1-2.0): 1.3-3.0.
6. The method according to claim 2, wherein in step (2), the organic solvent is selected from toluene.
7. The preparation method according to claim 2, wherein in the step (2), the compound 3 is reacted with the lawsen reagent at 40-100 ℃ for 12-16 hours; the mol ratio of the compound 3 to the Lawson reagent is (1.5-3.0): 0.8-1.2.
8. The preparation method according to claim 2, wherein in the step (3), the compound 4 and the compound 5 are dissolved in a mixed solvent, hydrochloric acid solution and acetic acid are added for reaction at 60-90 ℃ for 0.5-3 hours, the solvent is distilled off, then the organic solvent is added, and 10% NaOH solution is used for adjusting the pH value to 8-9 for reaction at 60-90 ℃ for 4-22 hours; the molar ratio of the compound 4 to the compound 5 is (0.6-1.8): 1.
9. The method according to claim 8, wherein the mixed solvent is alcohol or water, and the organic solvent is ethanol.
10. The method of claim 1, wherein the small molecule is selected from the group consisting of:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310677135.0A CN116730936A (en) | 2023-06-08 | 2023-06-08 | Preparation method of small molecule for promoting interaction of FXR protein and Caspase8 protein |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310677135.0A CN116730936A (en) | 2023-06-08 | 2023-06-08 | Preparation method of small molecule for promoting interaction of FXR protein and Caspase8 protein |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116730936A true CN116730936A (en) | 2023-09-12 |
Family
ID=87907394
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310677135.0A Pending CN116730936A (en) | 2023-06-08 | 2023-06-08 | Preparation method of small molecule for promoting interaction of FXR protein and Caspase8 protein |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116730936A (en) |
-
2023
- 2023-06-08 CN CN202310677135.0A patent/CN116730936A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104159898B (en) | For the preparation of the method for the fluoro-1H-pyrazolo-pyridines of 5-replacing | |
| CN109438405B (en) | Synthetic method of 3- (benzyloxy) -4-oxo-4H-pyran-2-carboxylic acid | |
| CN107365275B (en) | High purity celecoxib | |
| CN114805314B (en) | Synthesis method of Entecavir | |
| CN116730936A (en) | Preparation method of small molecule for promoting interaction of FXR protein and Caspase8 protein | |
| CN114671859B (en) | Preparation method of rosuvastatin calcium and intermediate thereof | |
| CN113583003A (en) | Vardenafil analogue and synthetic method and application thereof | |
| WO1998057923A1 (en) | New production process | |
| CN111499622A (en) | Preparation method of medicine for treating bile duct cancer | |
| CN111377867B (en) | Intermediate for synthesizing 2- (1-alkyl-1H-pyrazol-4-yl) morpholine and preparation method and application thereof | |
| US20050245742A1 (en) | Process for the preparation of zaleplon | |
| CN115417876B (en) | Intermediate compound of barytinib | |
| CN111635368B (en) | Preparation method of amine compound | |
| CN109153652A (en) | The preparation process of 1- (aryl methyl) quinazoline -2,4 (1H, 3H)-diketone | |
| CN109970673B (en) | Preparation method of parecoxib sodium impurity | |
| JPH0558985A (en) | Production of cyanoguanidine derivative | |
| CN115724793A (en) | Preparation method of 2-bromoisonicotinic acid nitrile | |
| CN106432095B (en) | The preparation of -3 (2H) -one of pimobendan key intermediate 6- (3,4- diamino-phenyl) -5- methyl -4,5- dihydrogen dazin | |
| JP4261839B2 (en) | Method for producing aminoimidazole compound | |
| KR940011527B1 (en) | Improve method diarkyl propanedi imidate dihydrohalaide | |
| JP5137576B2 (en) | Method for sulfonation of 1,2-benzisoxazole-3-acetic acid | |
| CN113698346A (en) | Preparation method of impurity B in blonanserin process | |
| JP4263427B2 (en) | Halogeno-4-dihydroxymethylpyridine, process for producing the same and process for producing halogeno-4-pyridinecarbaldehyde using the same | |
| CN111592471A (en) | Method for synthesizing cephalosporin active ester intermediate through bromination reaction | |
| CN117500789A (en) | Preparation method of pyridine borate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |