WO2021139795A1 - 吡咯烷基脲衍生物的制备方法 - Google Patents
吡咯烷基脲衍生物的制备方法 Download PDFInfo
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- WO2021139795A1 WO2021139795A1 PCT/CN2021/070962 CN2021070962W WO2021139795A1 WO 2021139795 A1 WO2021139795 A1 WO 2021139795A1 CN 2021070962 W CN2021070962 W CN 2021070962W WO 2021139795 A1 WO2021139795 A1 WO 2021139795A1
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- 238000000034 method Methods 0.000 title abstract description 10
- MZVRPCYUUFGMLJ-UHFFFAOYSA-N pyrrolidin-1-ylurea Chemical class NC(=O)NN1CCCC1 MZVRPCYUUFGMLJ-UHFFFAOYSA-N 0.000 title abstract description 4
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 62
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 52
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 50
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 39
- 239000003153 chemical reaction reagent Substances 0.000 claims description 35
- 239000002904 solvent Chemical group 0.000 claims description 30
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical group CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 26
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 26
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 25
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical group [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical group CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical group CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
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- -1 cinnamyl palladium chloride dimer Chemical class 0.000 claims description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 10
- SAHIZENKTPRYSN-UHFFFAOYSA-N [2-[3-(phenoxymethyl)phenoxy]-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound O(C1=CC=CC=C1)CC=1C=C(OC2=NC(=CC(=C2)CN)C(F)(F)F)C=CC=1 SAHIZENKTPRYSN-UHFFFAOYSA-N 0.000 claims description 8
- 239000000463 material Substances 0.000 claims description 8
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- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 7
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- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical group C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
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- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
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- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 3
- ASUDFOJKTJLAIK-UHFFFAOYSA-N 2-methoxyethanamine Chemical compound COCCN ASUDFOJKTJLAIK-UHFFFAOYSA-N 0.000 claims description 3
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- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 3
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- SUDBRAWXUGTELR-HPFNVAMJSA-N 5-[[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxymethyl]-1h-pyrimidine-2,4-dione Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OCC1=CNC(=O)NC1=O SUDBRAWXUGTELR-HPFNVAMJSA-N 0.000 claims description 2
- BCKAVKOEGXBNTM-UHFFFAOYSA-N C1(=CC=CC=C1)C1=C([C-](C=C1)P(=O)=O)C1=CC=CC=C1.[CH-]1C=CC=C1.[Fe+2] Chemical compound C1(=CC=CC=C1)C1=C([C-](C=C1)P(=O)=O)C1=CC=CC=C1.[CH-]1C=CC=C1.[Fe+2] BCKAVKOEGXBNTM-UHFFFAOYSA-N 0.000 claims description 2
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- TWKVUTXHANJYGH-UHFFFAOYSA-L allyl palladium chloride Chemical class Cl[Pd]CC=C.Cl[Pd]CC=C TWKVUTXHANJYGH-UHFFFAOYSA-L 0.000 claims description 2
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- SGUAFYQXFOLMHL-UHFFFAOYSA-N 2-hydroxy-5-{1-hydroxy-2-[(4-phenylbutan-2-yl)amino]ethyl}benzamide Chemical compound C=1C=C(O)C(C(N)=O)=CC=1C(O)CNC(C)CCC1=CC=CC=C1 SGUAFYQXFOLMHL-UHFFFAOYSA-N 0.000 description 1
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- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical class [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
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- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 101150117329 NTRK3 gene Proteins 0.000 description 1
- 102100033857 Neurotrophin-4 Human genes 0.000 description 1
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- 102000001253 Protein Kinase Human genes 0.000 description 1
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- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 description 1
- 102000005937 Tropomyosin Human genes 0.000 description 1
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- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- VEZXCJBBBCKRPI-UHFFFAOYSA-N beta-propiolactone Chemical compound O=C1CCO1 VEZXCJBBBCKRPI-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
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- MIHRVXYXORIINI-UHFFFAOYSA-N ethyl 2-cyanopropionate Chemical compound CCOC(=O)C(C)C#N MIHRVXYXORIINI-UHFFFAOYSA-N 0.000 description 1
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- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 1
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- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
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- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
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- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
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- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- RSIJVJUOQBWMIM-UHFFFAOYSA-L sodium sulfate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]S([O-])(=O)=O RSIJVJUOQBWMIM-UHFFFAOYSA-L 0.000 description 1
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- 230000001225 therapeutic effect Effects 0.000 description 1
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- LSGOVYNHVSXFFJ-UHFFFAOYSA-N vanadate(3-) Chemical compound [O-][V]([O-])([O-])=O LSGOVYNHVSXFFJ-UHFFFAOYSA-N 0.000 description 1
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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
- C07D405/14—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 three or more hetero rings
-
- 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
Definitions
- the present invention relates to a preparation method of a pyrrolidinyl urea derivative as a TrkA inhibitor, as well as an intermediate compound of the compound of formula (I) and a preparation method thereof.
- Tropomyosin-related kinase is a high-affinity receptor tyrosine activated by a group of soluble growth factors called nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophic factor (NT) Acid kinases, its family consists of three members (TrkA, TrkB, TrkC). NGF, BDNF, and NT-4/5 play an important role in the maintenance of neuronal cell signal, neuronal cell signal transmission, cell proliferation, cell differentiation, cell survival and many other physiological regulation processes through the receptor Trk.
- NGF nerve growth factor
- BDNF brain-derived neurotrophic factor
- NT neurotrophic factor Acid kinases
- TrkA inhibitor of the present invention can solve the treatment needs of pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases.
- WO2015175788 patent reports a single compound having inhibitory activity against TrkA and a pharmaceutically acceptable salt thereof.
- WO2012158413, WO2016116900, WO2016021629, WO2017006953 patents report a series of compounds with inhibitory activity against TrkA, including the pyrrolidinyl urea structure used in the present invention.
- the present invention provides a method for preparing the compound of formula (I),
- Step 1 Reacting a compound of formula SM3-9 and a compound of formula SM3-10 to obtain a compound of formula SM3-11,
- Step 2 Reacting the intermediate compound obtained by reacting the compound of formula SM1 and the compound of formula 1-1 with the compound of formula SM2 to obtain the compound of formula 1-2,
- Reagent P is selected from acetonitrile
- Reagent S-1 is selected from potassium acetate
- Reagent S-2 is selected from tricyclohexylphosphorus, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2,4,6-triisopropyl-1,1-biphenyl, 2-(Dicyclohexylphosphino)-3,6-dimethoxy-2-4-6-triisopropyl-1,1-biphenyl, triphenylphosphine and 2-dicyclohexylphosphine-2 ,4,6-Triisopropylbiphenyl;
- the catalyst U is selected from the group consisting of palladium acetate, diphenylphosphoferrocene palladium dichloride, tetrakistriphenylphosphonium palladium, allyl palladium chloride dimer, cinnamyl palladium chloride dimer and palladium trifluoroacetate;
- the base T is selected from sodium carbonate, cesium carbonate and potassium carbonate;
- Solvent V is selected from dioxane, methylcyclopentyl ether, toluene, methyltetrahydrofuran and tetrahydrofuran.
- the above-mentioned preparation method includes the following reaction route:
- Reagent A is selected from 2-methoxyethylamine
- Solvent B is selected from tetrahydrofuran
- Reagent C is selected from acetyl chloride
- Reagent D is selected from acetyl chloride
- Solvent E is selected from ethanol
- the reducing agent F is selected from the group consisting of lithium aluminum tetrahydrogen (flaky), borane tetrahydrofuran solution and borane dimethyl sulfide complex;
- Solvent G is selected from tetrahydrofuran
- Reagent H is selected from sulfonic acid isocyanates
- Reagent I is selected from tert-butanol
- the base J is selected from triethylamine and diisopropylethylamine
- Solvent K is selected from dioxane and dichloromethane
- Reagent L is selected from phthaloyl potassium salt, sodium hydrogen, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate and 1,8-diazabicycloundec-7-ene/phthalamide ;
- Solvent M is selected from N,N-dimethylformamide, tetrahydrofuran, methanol, dioxane and dimethyl sulfoxide;
- Reagent N is selected from hydrazine hydrate
- Solvent O is selected from ethanol
- Reagent Q is selected from p-toluenesulfonic acid, hydrochloric acid and trifluoroacetic acid;
- the solvent R is selected from tetrahydrofuran, dichloromethane and ethyl acetate;
- the base W is selected from pyridine, triethylamine, diisopropylethylamine and sodium bicarbonate;
- Solvent X is selected from dichloromethane, N,N-dimethylformamide, tetrahydrofuran and ethyl acetate;
- the base Y is selected from sodium carbonate, diisopropylethylamine, triethylamine, pyridine, sodium bicarbonate, potassium carbonate and sodium hydroxide;
- Solvent Z is selected from tetrahydrofuran/water, methyltetrahydrofuran, dichloromethane and methyltetrahydrofuran/water.
- the temperature range of the reaction system is controlled to be 65 ⁇ 5°C.
- the molar ratio of compound SM3-9 to compound SM3-10 is 1:1.2-2.
- the molar ratio of the compound SM1 to the catalyst U is 1:0.05-0.1.
- the temperature range of the reaction system is controlled to be 0 ⁇ 5°C when feeding materials into the reaction system.
- the molar ratio of compound SM3-3 to reagent C is 1:12-17.
- the temperature range of the reaction system is controlled to be 0 ⁇ 5°C.
- the molar ratio of compound SM3-5 to reducing agent F is 1:2-4.
- the temperature range of the reaction system is controlled to be 15 ⁇ 5°C when feeding materials into the reaction system.
- the temperature range of the reaction system is controlled to be 20 ⁇ 5°C.
- the temperature range of the reaction system is controlled to be 80 ⁇ 5°C.
- the pH is controlled at 2.7-3.5 when acid is used in the post-treatment to adjust the pH.
- the temperature range of the reaction system is controlled to be 35 ⁇ 5°C during the post-treatment and pH adjustment.
- the molar ratio of compound SM3-8 to reagent N is 1:1.5-2.
- the molar ratio of compound SM3-11 to reagent Q is 1:2.5-4.
- the temperature of the reaction system is controlled to be 5 ⁇ 5°C.
- the reaction time is 1.5 ⁇ 0.5 hours after reagents are added.
- the molar ratio of compound 1-4 to base Y is 1:5.
- the intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those skilled in the art.
- Well-known equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
- the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the field.
- SXRD single crystal X-ray diffraction
- the cultivated single crystal is collected with a Bruker D8 venture diffractometer to collect diffraction intensity data
- the light source is CuK ⁇ radiation
- the scanning method After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure to confirm the absolute configuration.
- the process for synthesizing the compound of formula (I) and its intermediates provided by the present invention has the beneficial effects that the raw materials are cheap and easy to obtain, overcome the shortcomings of separation and purification difficulties and difficult industrialization, and avoid national supervision of highly toxic methanesulfonyl chloride, easy Combustible and explosive sodium azide and palladium-carbon hydrogenation reduction reaction are not suitable for scale-up production steps, the total synthesis route is shortened, waste discharge is reduced, and it is more economical and practical.
- the invention has high industrial application value and economic value in preparing the compound of formula (I) and its intermediates.
- step 1
- compound SM1-1 (1.5kg, 5.27mol, 1 equivalent) was dissolved in anhydrous toluene (22.5L), the temperature was reduced to -70 ⁇ -78°C, and n-butyllithium (2.53L, 2.50 M n-hexane solution, 1.1 equivalents), the reaction solution was stirred at this temperature for 1 hour, and oxetanone (455.32g, 6.32mol, 1.2 equivalents) in toluene (900mL) was added dropwise. After the addition, the reaction solution Slowly increase the temperature to 25°C and keep the reaction for 16 hours.
- diethylaminosulfur trifluoride (32.54g, 2.68mol, 354.54mL, 1.55 equivalents) was dissolved in anhydrous dichloromethane (600mL), and compound SM1-2 (400g, 1.73mol, 1 equivalent) in anhydrous dichloromethane (2000 mL). After the addition was completed, the reaction solution was slowly warmed to 25°C and stirring continued for 1 hour. The reaction solution was cooled to 0°C, 5L water was added, and it was extracted with dichloromethane (5L*3). The combined organic phase was dried with anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure.
- compound SM3-7 (1.41kg, 71% content, 3.0mol, 1 equivalent) was dissolved in N,N-dimethylformamide (5000mL), and phthaloyl potassium salt (747g, 4.0 mol, 1.3 equivalents), the reaction solution was heated to 70°C and stirred for 8 hours. The temperature was lowered, the reaction solution was filtered through Celite, and the organic solvent was removed under reduced pressure. The obtained residue was dissolved in 2000 mL of tetrahydrofuran, and the pH was adjusted to 2.7-3.5 with 0.5 M aqueous hydrochloric acid solution, and the temperature was raised to 40° C. and stirring was continued for 1 hour.
- N,N-dimethylformamide 5000mL
- phthaloyl potassium salt 747g, 4.0 mol, 1.3 equivalents
- compound SM5-8 (600g, 60% content, 0.92mol, 1 equivalent) was dissolved in ethanol (7.2L), hydrazine hydrate (108.7g, 1.85mol, 2 equivalents) was added, and the reaction solution was heated to 70 Stirring was continued for 1 hour at °C. Cool, filter, remove the organic solvent under reduced pressure, combine 6 batches of crude product obtained by adding methyl tert-butyl ether (6000 mL), filter, and remove the organic solvent under reduced pressure to obtain 1.35 kg of compound SM3-9 (yield: 92.0% ).
- reaction solution was cooled to room temperature, filtered through celite, the filter cake was washed with ethyl acetate (5L), the combined filtrate was added to saturated brine (10L) for separation, and the aqueous phase was extracted with ethyl acetate (10L*2).
- This experiment uses Cisbio's homogeneous time-resolved fluorescence conjugate energy transfer ( Method) for activity detection.
- the enzyme, biotin-labeled peptide substrate, ATP, and detection compound are mixed, and the reaction is incubated.
- ethylenediaminetetraacetic acid was added to terminate the reaction, and at the same time, Eu-labeled antibody and streptavidin-labeled XL665 were added for reaction and detection.
- the data are represented by the readings of the fluorescence signal at 665nm and 620nm, where a high ratio of 665nm/620nm indicates higher activity, and a low ratio of 665nm/620nm indicates that the activity is inhibited.
- Compound dilution 4-fold dilution of the test compound, a total of 10 concentrations, the final system concentration from 10 ⁇ M to 0.038nM;
- the buffer is 20mM Hepes (pH 7.5), 10mM MgCl 2 , 1mM EGTA, 0.01% Brij35, 0.1mM sodium vanadate, 0.02g/mL BSA, 2mM DTT, 1% DMSO 10 ⁇ L reaction system, including 15nM TrkA kinase, 0.3 ⁇ M biotin-TK peptide (biotin-labeled tyrosine kinase substrate polypeptide), 100 ⁇ M ATP, incubate at 23°C for 120 minutes. Place the reaction point on P81 ion exchange paper (Whatman#3698-915), wash the filter membrane thoroughly with 0.75% phosphoric acid, and measure the radioactive phosphorylated substrate remaining on the filter membrane. The kinase activity data is expressed as the percentage of kinase activity in the test sample compared to the vehicle (DMSO) reaction.
- the inhibitory activity of the test compound on different isoenzymes of human cytochrome P450 is determined.
- test compound Prepare test compound, standard inhibitor (100 ⁇ final concentration) and mixed substrate working solution; take out the microsomes frozen at -80°C in the refrigerator and thaw.
- the test compound was prepared into a clear solution or homogeneous suspension, and the rats were given a single intravenous injection and oral administration.
- C 0 is the initial concentration
- T 1/2 is the elimination half-life
- Vd ss is the steady-state apparent volume of distribution
- Cl is the total clearance rate
- AUC 0-inf is the plasma concentration from time 0 to extrapolation to infinity -The area under the time curve
- C max is the peak concentration
- T max is the peak time.
- test The purpose of the test is to test the pharmacokinetic characteristics of non-rodent animals after intravenous injection and oral administration of the test compound.
- the test compound is formulated into a clear solution or homogeneous suspension and given to beagle dogs by a single intravenous injection or oral administration .
- the solvent was a certain proportion of dimethyl sulfoxide HP- ⁇ -cyclodextrin solution or a certain proportion of ethanol, polyethylene glycol 400 and physiological saline solution, vortexed and sonicated to prepare a clear solution of 2 mg/kg, micro
- the pore filter membrane is used for use after filtration;
- the oral solvent is HP- ⁇ with a certain proportion of dimethyl sulfoxide Cyclodextrin solution or a certain ratio of sodium carboxymethyl cellulose solution, the test compound is mixed with the solvent, vortexed and sonicated to prepare a 3 mg/mL homogeneous suspension for later use.
- Beagle dogs were given 2 mg/kg intravenously, 15 mg/kg orally administered, a certain amount of whole blood samples were collected, centrifuged at 3000g for 10 minutes, the supernatant was separated to obtain a plasma sample, and 10 times the volume of acetonitrile solution containing internal standard was added to precipitate the protein. The supernatant was taken by centrifugation and the sample was injected.
- the blood drug concentration was quantitatively analyzed by LC-MS/MS analysis method, and the pharmacokinetic parameters were calculated by Phoenix WinNonlin software (Pharsight, USA), such as peak concentration, peak time, clearance rate, half-life, Area under the drug-time curve, bioavailability, etc.
- C 0 is the initial concentration
- T 1/2 is the elimination half-life
- Vd ss is the steady-state apparent volume of distribution
- Cl is the total clearance rate
- AUC 0-inf is the plasma concentration from time 0 to extrapolation to infinity -The area under the time curve
- C max is the peak concentration
- T max is the peak time.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明公开了一种作为TrkA抑制剂的吡咯烷基脲衍生物的制备方法,还公开了式(I)化合物的中间体化合物及其制备方法。
Description
本申请主张如下优先权
CN202010027384.1,申请日:2020-01-10。
本发明涉及一种作为TrkA抑制剂的吡咯烷基脲衍生物的制备方法,还涉及式(I)化合物的中间体化合物及其制备方法。
原肌球蛋白相关激酶(Trk)是由称为神经增长因子(NGF)、脑源性神经营养因子(BDNF)、神经营养因子(NT)的一群可溶性增长因子所激活的高亲和力受体酪氨酸激酶,其家族由三个成员(TrkA、TrkB、TrkC)组成。NGF、BDNF、NT-4/5通过受体Trk在神经元细胞的信号维持、神经元细胞的信号传递、细胞增殖、细胞分化、细胞存活等许多生理学调节过程中发挥重要作用。有许多证据显示NGF/Trk信号通路的抑制剂在疼痛的许多临床前模型中有效;还显示NGF/Trk信号通路的抑制剂在炎症性疾病的许多临床前模型中有效。此外,Trk激酶的过度表达、激活、扩增和/或突变与许多肿瘤或癌症相关。因此,Trk成为了一类重要治疗靶点,吸引了广泛的研发兴趣。本发明所述的TrkA抑制剂可以解决疼痛、癌症、炎症、神经变性疾病以及某些感染性疾病的治疗需求。
WO2015175788专利中报道了对TrkA有抑制活性的单一化合物及其药学上可接受的盐。WO2012158413、WO2016116900、WO2016021629、WO2017006953专利中报道了一系列对TrkA有抑制活性的化合物,包含本发明中使用的吡咯烷基脲结构。
发明内容
本发明提供了式(Ⅰ)化合物的制备方法,
其包含如下步骤:
步骤1:使式SM3-9化合物和式SM3-10化合物反应以获得式SM3-11化合物,
步骤2:使式SM1化合物和式1-1化合物反应得到的中间体化合物和式SM2化合物反应以获得式1-2化合物,
其中,
试剂P选自乙腈;
试剂S-1选自乙酸钾;
试剂S-2选自三环己基磷、2-二叔丁基膦基-3,4,5,6-四甲基-2,4,6-三异丙基-1,1-联苯、2-(二环己基膦基)-3,6-二甲氧基-2-4-6-三异丙基-1,1-联苯、三苯基磷和2-二环己基磷-2,4,6-三异丙基联苯;
催化剂U选自醋酸钯、二苯基磷二茂铁二氯化钯、四三苯基磷钯、烯丙基氯化钯二聚物、肉桂基氯化钯二聚体和三氟乙酸钯;
碱T选自碳酸钠、碳酸铯和碳酸钾;
溶剂V选自二氧六环、甲基环戊基醚、甲苯、甲基四氢呋喃和四氢呋喃。
本发明的一些方案中,上述的制备方法,其包含如下反应路线:
其中,
试剂A选自2-甲氧基乙胺;
溶剂B选自四氢呋喃;
试剂C选自乙酰氯;
试剂D选自乙酰氯;
溶剂E选自乙醇;
还原剂F选自四氢铝锂(片状)、硼烷四氢呋喃溶液和硼烷二甲硫醚复合物;
溶剂G选自四氢呋喃;
试剂H选自磺酸异氰酸酯;
试剂I选自叔丁醇;
碱J选自三乙胺和二异丙基乙胺;
溶剂K选自二氧六环和二氯甲烷;
试剂L选自邻苯二甲酰基钾盐、钠氢、叔丁醇钾、叔丁醇钠、碳酸钾和1,8-二氮杂二环十一碳-7-烯/邻苯二甲酰胺;
溶剂M选自N,N-二甲基甲酰胺、四氢呋喃、甲醇、二氧六环和二甲基亚砜;
试剂N选自水合肼;
溶剂O选自乙醇;
试剂Q选自对甲苯磺酸、盐酸和三氟乙酸;
溶剂R选自四氢呋喃、二氯甲烷和乙酸乙酯;
碱W选自吡啶、三乙胺、二异丙基乙胺和碳酸氢钠;
溶剂X选自二氯甲烷、N,N-二甲基甲酰胺、四氢呋喃和乙酸乙酯;
碱Y选自碳酸钠、二异丙基乙基胺、三乙胺、吡啶、碳酸氢钠、碳酸钾和氢氧化钠;
溶剂Z选自四氢呋喃/水、甲基四氢呋喃、二氯甲烷和甲基四氢呋喃/水。
本发明的一些方案中,上述的制备方法,其中,制备化合物SM3-11的步骤中,控制反应体系温度范围为65±5℃。
本发明的一些方案中,上述的制备方法,其中,化合物SM3-9与化合物SM3-10的摩尔比为1:1.2~2。
本发明的一些方案中,上述的制备方法,其中,化合物SM1与催化剂U的摩尔比为1:0.05~0.1。
本发明的一些方案中,上述的制备方法,其中,制备化合物SM3-3的步骤中,向反应体系中投料时,控制反应体系温度范围为0±5℃。
本发明的一些方案中,上述的制备方法,其中,化合物SM3-3与试剂C的摩尔比为1:12~17。
本发明的一些方案中,上述的制备方法,其中,制备化合物SM3-5的步骤中,向反应体系中投料时,控制反应体系温度范围为0±5℃。
本发明的一些方案中,上述的制备方法,其中,制备化合物SM3-6的步骤中,化合物SM3-5与还原剂F的摩尔比为1:2~4。
本发明的一些方案中,上述的制备方法,其中,制备化合物SM3-7的步骤中,向反应体系中投料时,控制反应体系温度范围为15±5℃。
本发明的一些方案中,上述的制备方法,其中,制备化合物SM3-7的步骤中,试剂投料完毕后,控制反应体系温度范围为20±5℃。
本发明的一些方案中,上述的制备方法,其中,制备化合物SM3-7的步骤中,反应完成后,保持在氮气环境下过滤。
本发明的一些方案中,上述的制备方法,其中,制备化合物SM3-7的步骤中,试剂投料完毕后,控制反应体系温度范围为80±5℃。
本发明的一些方案中,上述的制备方法,其中,制备化合物SM3-8的步骤中,后处理用酸调节pH时控制在2.7~3.5。
本发明的一些方案中,上述的制备方法,其中,制备化合物SM3-8的步骤中,后处理调节pH时控制反应体系温度范围为35±5℃。
本发明的一些方案中,上述的制备方法,其中,化合物SM3-8与试剂N的的摩尔比为1:1.5~2。
本发明的一些方案中,上述的制备方法,其中,化合物SM3-11与试剂Q的摩尔比为1:2.5~4。
本发明的一些方案中,上述的制备方法,其中,制备化合物1-4的步骤中,向反应体系中投料时,控制反应体系温度为5±5℃。
本发明的一些方案中,上述的制备方法,其中,制备化合物1-4的步骤中,试剂投料完毕后,反应时间为1.5±0.5小时。
本发明的一些方案中,上述的制备方法,其中,化合物1-4与碱Y的摩尔比为1:5。
定义和说明
除非另有说明,本文所用的下列术语和短语旨在含有下列含义。一个特定的短语或术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的,而应该按照普通的含义去理解。当本文出现商品名时,旨在指代其对应的商品或其活性成分。
本发明的中间体化合物可以通过本领域技术人员所熟知的多种合成方法来制备,包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式,优选的实施方式包括但不限于本发明的实施例。
本发明具体实施方式的化学反应是在合适的溶剂中完成的,所述的溶剂须适合于本发明的化学变化及其所需的试剂和物料。为了获得本发明的化合物,有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
本领域任何合成路线规划中的一个重要考量因素是为反应性官能团(如本发明中的氨基)选择合适的保护基。
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构,如果本发明涉及化合物的绝对构型,则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD),把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据,光源为CuKα辐射,扫描方式:
扫描,收集相关数据后,进一步采用直接法(Shelxs97)解析晶体结构,便可以确证绝对构型。
下面会通过实施例具体描述本发明,这些实施例并不意味着对本发明的任何限制。
本发明所使用的所有溶剂是市售的,无需进一步纯化即可使用。
本发明采用下述缩略词:aq代表水;eq代表当量、等量;DCM代表二氯甲烷;PE代表石油醚;DMF代表N,N-二甲基甲酰胺;DMSO代表二甲亚砜;EtOAc代表乙酸乙酯;EtOH代表乙醇;MeOH代表甲醇;CBz代表苄氧羰基,是一种胺保护基团;BOC代表叔丁氧羰基是一种胺保护基团;HOAc代表乙酸;r.t.代表室温;Rt代表保留时间;O/N代表过夜;THF代表四氢呋喃;Boc
2O代表二叔丁基二碳酸酯;TFA代表三氟乙酸。
技术效果
本发明给出的合成式(I)化合物及其中间体的工艺,有益效果为:原料价格便宜易得,克服分离纯化困难以及不易工业化等缺点,避免了国家监管剧毒品甲烷磺酰氯、易燃易爆叠氮钠和钯碳氢化还原反应等不适于放大生产步骤,总合成路线缩短,减少废物排放,更经济实用。本发明在制备式(I)化合物及其中间体方面,具有很高的工业应用价值和经济价值。
为了更好的理解本发明的内容,下面结合具体实施例来做进一步的说明,但具体的实施方式并不是对本发明的内容所做的限制。
实施例1:化合物SM1的制备
步骤1:
氮气保护下,将化合物SM1-1(1.5kg,5.27mol,1当量)溶于无水甲苯(22.5L)中,降温至-70~-78℃,滴加正丁基锂(2.53L,2.50M正己烷溶液,1.1当量),反应液在该温度下搅拌1小时,滴加氧杂环丁酮(455.32g,6.32mol,1.2当量)的甲苯(900mL)溶液,滴加完毕后,反应液缓慢升温至25℃,并保持继续反应16小时。缓慢加入饱和氯化铵水溶液(10L),用二氯甲烷(7.5L*2)萃取,合并后的有机相用饱和食盐水洗涤,无水硫酸镁干燥,过滤,减压除去有机溶剂,所得粗产物经硅胶柱层析分离纯化(石油醚/四氢呋喃=8/1至5/1),得到1.05kg化合物SM1-2(收率:43.0%)。
1HNMR(400MHz,CDCl
3):8.86(s,2H),5.03-4.96(m,5H)。
步骤2:
冰水浴保护下,将二乙氨基三氟化硫(432.54g,2.68mol,354.54mL,1.55当量)溶于无水二氯甲烷(600mL)中,滴加化合物SM1-2(400g,1.73mol,1当量)的无水二氯甲烷(2000mL)溶液。滴加完毕后,反应液缓慢升温至25℃继续搅拌1小时。反应液降温至0℃,加入5L水,用二氯甲烷(5L*3)萃取,合并后的有机相用无水硫酸钠干燥,过滤,减压除去有机溶剂,合并四批反应液所得粗产物经硅胶柱层析分离纯化(石油醚/乙酸乙酯=1/0至10/1),所得产物继续用1.5L石油醚重结晶,过滤,得到1.08kg化合物SM1(收率:67.1%)。
1HNMR(400MHz,CDCl
3):8.891(s,2H),5.18-5.05(m,4H)。
实施例2:化合物SM2的制备
步骤3:
将化合物SM2-1(12.8kg,118.36mol,1.0当量)加入到N,N-二甲基甲酰胺(10.0-15.0kg)中,加入2-氰基丙酸乙酯(15.0kg,118.36mol,1.0当量),反应液升温至100-130℃继续搅拌10-15小时。反应液降温至室温,加入47.2kg甲基叔丁基醚,继续在25℃下搅拌2-3小时,过滤,滤饼用2-5kg甲基叔丁基醚洗涤,所得固体经真空干燥得到13.1kg化合物SM2-2(收率:59.0%)。
1HNMR(300MHz,DMSO_d
6):9.62(s,1H),7.49-7.37(m,4H),7.21-7.16(m,1H),5.24(s,2H),1.69(s,3H)。
步骤4:
将化合物SM2-2(8.58kg,45.35mol,1.0当量)加入到N,N-二甲基甲酰胺(15.0-20.0kg)中,加入二异丙基乙胺(7.0kg,54.16mol,9.4L,1.2当量),反应液降温至-5-15℃,在该温度下滴加N-苯基双(三氟甲烷磺酰)亚胺(17.0kg,47.59mol,1.05当量),滴加完毕后,反应液升温至25℃继续搅拌10-15小时。反应液中加入60-80kg的10%的碳酸钠水溶液和15.0-20.0kg的甲基叔丁基醚,分液,有机相用50-80kg的10%的碳酸钠水溶液洗涤两次,用50-70kg的饱和氯化铵水溶液洗涤三次,用50-70kg的饱和食盐水洗涤一次,减压除去有机溶剂,所得粗产物用15L石油醚重结晶,过滤,所得固体经真空干燥得到13.4kg化合物SM2(收率:92.0%)。
1HNMR(300MHz,DMSO_d
6):7.53-7.49(m,4H),7.41-7.38(m,1H),5.67(s,2H),1.89(s,3H)。
实施例3:化合物SM3的制备
步骤5:
将化合物SM3-1(49.5-50.5kg,329.81-336.47mol,1当量)加入到乙酰氯(275.0-280.0kg,3.50-3.57kmol,10当量)中,反应液升温至50℃继续搅拌12-24小时。减压除去有机溶剂,所得粗产物加入甲基叔丁基醚(185.0-190.0kg),浓缩,重复三次,粗产物继续加入到甲基叔丁基醚(185.0-190.0kg)中并在室温下搅拌2小时,过滤,滤饼用37.0-40.0kg甲基叔丁基醚洗涤,干燥滤饼得到60.7kg化合物SM3-2(收率:84.3%)。
1H NMR(300MHz,CDCl
3):5.70(s,2H),2.25(s,6H)。
步骤6:
将化合物SM3-2(60.0-60.5kg,277.59-279.90mol,1当量)加入到四氢呋喃(270.0-275.0kg)中,反应液降温至-5-5℃,滴加2-甲氧基乙胺(24.0-24.5kg,319.53-326.19mol,1.15当量),并保持反应液温度在-5-5℃,滴加完毕后,反应液升温至65℃并继续搅拌2-24小时。减压除去有机溶剂,所得粗产物加入甲基叔丁基醚(224.0-230.0kg),浓缩,重复三次,粗产物继续加入到甲基叔丁基醚(224.0-230.0kg)中并在室温下搅拌2小时,过滤,滤饼用45.0-50.0kg甲基叔丁基醚洗涤,得到78.4kg粗品化合物SM3-3(收率:95.8%)。
1H NMR(300MHz,DMSO_d
6):8.15(brs,1H),5.45(d,J=2.4Hz,1H),5.37(d,J=2.4Hz,1H),5.26(brs,1H),3.50(t,J=5.4Hz,2H),3.20(s,3H),2.96(t,J=5.4Hz,2H),2.09(s,3H),2.02(s,3H)。
步骤7:
将化合物SM3-3(78.3kg,268.84mol,1当量)加入到乙酰氯(360.0-365.0kg,4.59-4.65kmol,17当量)中,反应液升温至50℃继续搅拌12-24小时。减压除去有机溶剂,所得粗产物加入甲基叔丁基醚(290.0-300.0kg),浓缩,重复三次,粗产物继续加入到甲基叔丁基醚(232.0-240.0kg)和乙酸乙酯(140.0-145.0kg)中,用315.0-320.0kg 8%碳酸氢钠水溶液洗涤,水相用乙酸乙酯(282.0-290.0kg)萃取3次,合并后的有机相用(315.0-320.0kg)饱和食盐水洗涤,减压除去有机溶剂,所得粗产物加入乙醇(186.0-190.0kg),浓缩,重复两次,加入390.0-395.0kg乙醇,得到化合物SM3-4的乙醇溶液,该溶液不经进一步纯化直接用于下一步反应。
1H NMR(300MHz,DMSO_d
6):5.78(s,2H),3.60(m,2H),3.45(d,2H),3.23(s,3H),2.15(s,6H)。
步骤8:
将上述化合物SM3-4(73.5kg,268.99mol,1当量)的乙醇溶液降温至-5-5℃,滴加乙酰氯(150.0-155.0kg,1.91-1.97kmol,7当量),反应液升温至20-30℃继续搅拌5-24小时。加入活性碳(5.0-5.5kg),继续搅拌2-5小时。过滤,滤饼用乙醇(115.0-120.0kg)洗涤,减压除去有机溶剂,所得粗产物加入甲基叔丁基醚(240.0-250.0kg),浓缩,重复三次,粗产物继续加入到甲基叔丁基醚(240.0-250.0kg)中,继续搅拌2-5小时,过滤,滤饼用100.0-105.0kg甲基叔丁基醚洗涤,干燥,得到33.7kg化合物SM3-5(含量:88%,收率:66.0%)。
1HNMR(300MHz,DMSO_d
6):5.58(brs,2H),4.30(s,2H),3.53(m,2H),3.44(m,2H),3.21(s,3H)。
步骤9:
氮气保护下,将片状四氢铝锂(200g,5.29mol,4当量)溶于无水四氢呋喃(5000mL)中,滴加化合物SM3-5(284g,88%含量,1.32mol,1当量)的四氢呋喃(2000mL)溶液,反应液升温至60-70℃继续搅拌16小时。反应液冷却至20-30℃,依次加入十水硫酸钠(284g,1.32mol,1当量),水(284mL)和20%氢氧化钠水溶液(284mL),反应液升温至60℃继续搅拌1小时。过滤,滤饼用4000mL四氢呋喃洗涤两次,所得滤饼加入到4000mL四氢呋喃和500mL 20%的氢氧化钠水溶液中,加入500g无水硫酸钠,过滤,合并有机相,合并41批次有机相,减压除去有机溶剂,得到4.34kg化合物SM3-6(含量:83%,收率:41.2%)。
1HNMR(400MHz,DMSO_d
6):4.87(s,2H),3.95-3.93(m, 2H),3.27(s,3H),2.85-2.80(m,2H),2.61-2.49(m,2H),2.40-2.36(m,2H)。
步骤10:
氮气保护下,将磺酸异氰酸酯(614.6g,4.34mol,3.5当量)溶于无水1,4-二氧六环(800mL)中,降温至10-20℃,缓慢滴加叔丁醇((321.9g,4.34mol,3.5当量)溶于1,4-二氧六环(600mL)的溶液,保持内温在10-20℃,滴加完毕后继续搅拌0.5小时,所得溶液备用。冰水浴条件下,将化合物SM3-6(241g,83%含量,1.25mol,1当量)溶于无水1,4-二氧六环(4000mL)中,加入三乙胺(753g,7.44mol,6当量),然后缓慢滴加上述备用溶液,并保持反应液温度不超过20℃,滴加完毕后,反应液在25℃下搅拌4小时。氮气保护下过滤,滤饼用无水二氧六环洗涤一次,所得滤液中加入三乙胺(213g,2.1mol,1.7当量),反应液升温至82℃继续搅拌4小时。降温,减压除去有机溶剂,加入2000mL水和2000mL乙酸乙酯,分液,水相继续用2000mL乙酸乙酯萃取一次,合并后的有机相减压除去有机溶剂,合并12批次所得粗品经硅胶柱层析(石油醚至石油醚:乙酸乙酯=4:1)分离纯化,得到2.68kg化合物SM3-7(含量:71%,收率:39.6%)。
1HNMR(400MHz,DMSO_d
6):5.35-5.32(m,1H),4.73-4.70(m,1H),3.52-3.49(m,2H),3.12(s,3H),3.12-3.08(m,1H),3.02-2.98(m,1H),2.86-2.82(m,2H),2.73-2.70(m,2H),1.53(m,9H)。
步骤11:
氮气保护下,将化合物SM3-7(1.41kg,71%含量,3.0mol,1当量)溶于N,N-二甲基甲酰胺(5000mL)中,加入邻苯二甲酰基钾盐(747g,4.0mol,1.3当量),反应液升温至70℃继续搅拌8小时。降温,反应液经硅藻土过滤,减压除去有机溶剂,所得残余物用2000mL四氢呋喃溶解,用0.5M盐酸水溶液调节pH至2.7~3.5,升温至40℃继续搅拌1小时。冷却,用甲基叔丁基醚(4000mL)萃取,水相用20%碳酸钠水溶液调节pH至8~9,合并另外两个批次过滤,滤饼用水洗涤,干燥得6.0kg到化合物SM3-8(含量:60%,收率:81.0%)。
1H NMR(400MHz,DMSO_d
6):7.83-7.71(m,4H),5.25-5.22(m,1H),4.64-4.58(m,2H),3.52-3.46(m,2H),3.33(s,3H),3.24-3.20(m,1H),3.08-3.04(m,1H),2.95-2.88(m,1H),2.78-2.70(m,3H),1.38(s,9H)。
步骤12:
氮气保护下,将化合物SM5-8(600g,60%含量,0.92mol,1当量)溶于乙醇(7.2L)中,加入水合肼(108.7g,1.85mol,2当量),反应液升温至70℃继续搅拌1小时。冷却,过滤,减压除去有机溶剂,合并6批次所得粗产物中加入甲基叔丁基醚(6000mL),过滤,减压除去有机溶剂,得到1.35kg化合物SM3-9(收率:92.0%)。
1H NMR(400MHz,CDCl
3):4.79(s,1H),3.54-3.52(m,1H),3.32-3.29(m,2H),3.20(s,3H),3.11(s,1H),2.70-2.66(m,1H),2.51-2.40(m,3H),1.99-1.95(m,1H),1.42(s,9H)。
步骤13:
将化合物SM3-12(750g,3.00mol,1当量)和乙烯基三甲基硅烷(601.45g,6.00mol,870.40mL,2当量)溶于乙腈(1.8L)中,加入活化后的铜粉(9.53g,150.01mmol,0.05当量),反应液升温至65℃继续搅拌18小时。减压除去有机溶剂,合并4批次所得粗产物经硅胶柱层析(洗脱剂:0~3%乙 酸乙酯/石油醚)分离纯化,得到3.80kg化合物SM3-13(收率:90.5%)。
1H NMR(400MHz,CDCl
3):4.25-4.12(m,2H),2.93-2.90(m,1H),2.47-2.39(m,2H),1.24-1.13(m,3H),0.02(s,9H)。
步骤14:
-20℃下,将化合物SM3-13(1.27kg,3.63mol,1当量)溶于无水四氢呋喃(15L)中,慢慢滴入二异丁基氢化铝(1M的甲苯溶液,5.44L,1.5当量),滴完后反应液缓慢升温至10℃继续搅拌1小时。降温,缓慢滴加5L 2N的盐酸水溶液,并保持反应液温度不超过20℃,用乙酸乙酯萃取(8L*2),合并萃取后的有机相,用10L饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压除去有机溶剂,得到977.5g化合物SM3-10(收率:88.0%)。该化合物不经进一步纯化直接用于下一步反应。
步骤15:
将化合物SM3-9(690g,2.66mol,1当量)溶于乙腈(6.5L)中,加入化合物SM3-10(977.48g,3.19mol,1.2当量),反应液升温至65℃继续搅拌14小时。减压除去有机溶剂,合并另一批次所得粗产物经硅胶柱层析(洗脱剂:0~60%乙酸乙酯/石油醚~5%甲醇/乙酸乙酯)分离纯化,得到1.70kg化合物SM3-11(收率:98.0%)。
1H NMR(400MHz,CDCl
3):6.74(s,1H),6.50(s,1H),5.77(s,1H),5.64(s,1H),4.85(s,1H),4.48(s,1H),3.81-3.58(m,6H),3.41-3.38(m,2H),3.23(s,3H),1.19(s,9H)。
步骤16:
将化合物SM3-11(2.86kg,8.74mol,1当量)溶于无水四氢呋喃(22L)中,加入对甲苯磺酸(3.76kg,21.84mol,2.5当量),反应液升温至80℃继续搅拌2小时。冷却,过滤,滤饼用甲基叔丁基醚(300mL*2)洗涤,干燥,得到3.30kg化合物SM3(收率:66.1%)。
1H NMR(400MHz,MeOD):7.76-7.74(m,4H),7.30-7.28(m,4H),6.86-6.84(m,1H),6.78-6.75(m,1H),6.01-5.99(m,1H),5.11-5.09(m,1H),4.44-4.41(m,1H),4.15-4.11(m,2H),3.85-3.70(m,4H),3.62-3.59(m,2H),3.38(s,3H),2.40(s,6H)。
实施例4:化合物1的制备
步骤17:
氮气保护下,将化合物SM1(1.0kg,4.30mol,1当量)溶于无水二氧六环(30.0L)中,依次加入双联频哪醇硼酸酯(1.2kg,4.74mol,1.1当量),乙酸钾(840g,8.62mol,2当量),三环己基磷(120g,430.0mmol,0.1当量)和醋酸钯(100g,430mmol,0.1当量),反应液升温至90℃继续搅拌3小时,依次向反应液中加入水(5L),SM2(1.1kg,3.45mol,0.8当量),碳酸钠(1.0kg,8.62mol,2当量)和二苯基磷二茂铁二氯化钯(300g,430.0mmol,0.1当量),反应液在该温度下继续搅拌15-18小时。反应液冷却至室温,经硅藻土过滤,滤饼用乙酸乙酯(5L)洗涤,合并后的滤液 加入饱和食盐水(10L)分液,水相用乙酸乙酯(10L*2)萃取,减压浓缩合并后的有机相至30L,加入活性碳(2.0kg),无水硫酸镁(4.0kg)和金属消除剂(3-巯丙基官能团硅胶,2.0kg),升温至55℃继续搅拌18小时,反应液经硅藻土过滤,滤饼用乙酸乙酯(10L*2)洗涤,减压除去有机溶剂,所得粗产物加入到甲基叔丁基醚(5L)中,加入正庚烷(1L),继续在室温下搅拌15-18小时,过滤,滤饼用甲基叔丁基醚(500mL*2)洗涤,干燥,所得粗产物加入到乙腈(3.5L)中,加入水(15-17L),混合液升温至80℃继续搅拌15小时,过滤,滤饼用水(500mL*2)洗涤,干燥,得到0.47kg化合物1-2(收率:40.0%)。
1H NMR(400MHz,CDCl
3):9.20(s,2H),7.68-7.62(m,2H),7.57-7.53(m,2H),7.48-7.40(m,1H),5.29-5.13(m,4H),3.76(brs,2H),2.19(s,3H)。
步骤18:
氮气保护下,将化合物1-2(0.73kg,2.24mol,1当量)溶于无水二氯甲烷(15L)中,加入吡啶(0.54kg,6.74mol,3当量),冷却至0℃,滴加化合物1-3(0.46kg,2.92mol,1.3当量)的二氯甲烷(1.2L)溶液,并保持反应液内部温度不超过10℃,滴加完毕后,反应液在该温度下继续搅拌0.5-2小时。反应液中加入0.5N的盐酸水溶液(8L),分液,水相用二氯甲烷(8L)萃取,合并后的有机相用饱和食盐水(10L)洗涤,无水硫酸钠干燥,过滤,减压除去有机溶剂,得到0.90kg化合物1-4(收率:90.0%),该化合物不经进一步纯化直接用于下一步反应。
1H NMR(400MHz,CDCl
3):9.26(s,2H),7.64-7.40(m,6H),7.53-7.48(m,2H),7.32-7.29(m,1H),7.15-7.12(m,1H),5.31-5.12(m,4H),2.35(s,3H)。
步骤19:
化合物1-4(1.0kg,2.24mol,1当量)溶于无水四氢呋喃(10L)中,加入化合物SM3(1.28kg,2.24mol,1当量),滴加碳酸钠(1.19kg,11.23mol,5当量)的水(5.0L)溶液,反应液在室温下搅拌20小时。反应液中加入水(6.0L)和乙酸乙酯(6.0L),分液,水相用乙酸乙酯(6.0L*2)萃取,合并后的有机相用饱和食盐水(15.0L)洗涤,无水硫酸钠干燥,过滤,减压除去有机溶剂,所得粗产物加入到甲醇(6.5L)中,加入水(13L),混合液升温至40℃继续搅拌2-24小时,过滤,滤饼用水(2L*2)洗涤,继续加入到甲醇(8L)中,加入水(10L),混合液升温至40℃搅拌10-48小时,过滤,滤饼用水(2L*2)洗涤,干燥得到0.93kg化合物1(收率:71.6%)。
1H NMR(400MHz,MeOD):9.27(s,2H),7.61-7.50(m,4H),7.49-7.42(m,1H),6.64-6.59(m,1H),6.56-6.50(m,1H),5.84(m,1H),5.32-5.21(m,2H),5.12-5.02(m,2H),4.34-4.18(m,2H),3.55-3.53(t,J=5.2Hz,2H),3.37(s,3H),3.14-3.06(m,2H),2.89-2.64(m,3H),2.55-2.50(m,1H),2.23(s,3H)。
实验例1:TrkA酶活性测试
实验材料
TrkA Invitrogen-PV4114
TK检测试剂盒 Cisbio-62TK0PEJ
检测板 PerkinElmer-6007299
Envision PerkinElmer-2104
激酶反应缓冲液
20mM Hepes(pH 7.5),10mM MgCl
2(氯化镁),1mM EGTA,0.01%Brij35,0.1mM Orthovanadate(钒酸钠),0.02g/mL BSA(牛血清蛋白),2mM DTT(二硫苏糖醇),1%DMSO
实验方法
本次试验使用Cisbio公司的均相时间分辨的荧光共轭能量转移(
方法)进行活性检测。在检测板中,将酶、生物素标记的多肽底物、ATP以及检测化合物混合,孵育反应。反应后,加入乙二胺四乙酸终止反应,并同时加入Eu标记的抗体,链酶亲和素标记的XL665进行反应并检测。数据分别用荧光信号665nm和620nm的读数来表示,其中665nm/620nm的高比值表示活性较高,而665nm/620nm的低比值则表示活性受到抑制。
实验步骤
1.化合物稀释:待测化合物4倍进行稀释,共10个浓度,最终体系浓度从10μM至0.038nM;
2.在缓冲液为20mM Hepes(pH 7.5),10mM MgCl
2,1mM EGTA,0.01%Brij35,0.1mM钒酸钠,0.02g/mL BSA,2mM DTT,1%DMSO的10μL反应体系中,包括15nM TrkA激酶,0.3μMbiotin-TK peptide(生物素标记的酪氨酸激酶底物多肽),100μM ATP,在23℃孵育120分钟。将反应点在P81离子交换纸上(Whatman#3698-915),用0.75%的磷酸彻底清洗滤膜,测量残留在滤膜上的放射性磷酸化底物。激酶活性数据表示为与溶媒(DMSO)反应相比,测试样品中激酶活性的百分比。
3.IC
50和曲线拟合可以通过Graphpad软件Prism4获取。
实验结果
结果见表1。
表1式(I)化合物对TrkA酶抑制的IC
50值
化合物编号 | TrkA IC 50(nM) |
式(I)化合物 | 6.64 |
结果表明:式(I)化合物具有显著的TrkA酶抑制作用。
实验例2:细胞色素P450同工酶抑制活性测试
实验目的
测定受试化合物对人细胞色素P450同工酶不同亚型的抑制活性。
实验操作
准备受试化合物、标准抑制剂(100×最终浓度)和混合底物工作溶液;将冷冻于-80℃冰箱的微粒体取出解冻。将2μL的待测化合物和标准抑制剂溶液加至相应孔位,同时将2μL相应的溶剂加至无抑制剂对照孔位(NIC)和空白对照孔位(Blank)孔位;其次将20μL混合底物溶液加至相应孔位,Blank孔位除外(将20μL PB加至Blank孔位);准备人肝微粒体溶液(使用后标记日期立刻放回冰箱),随即将158μL人肝微粒体溶液加至所有孔位;将上述样品板放入37℃水浴预孵育,随即准备辅酶因子(NADPH)溶液;10分钟后,添加20μL NADPH溶液到所有孔位,样品板摇匀后,放入37℃水浴孵育10分钟;在相应时间点,加入400μL冷的乙腈溶液(内标为200ng/mL甲苯磺丁脲和拉贝洛尔)终止 反应;样品板混合均匀后,4000rpm离心20分钟,沉淀蛋白质;取200μL上清加至100μL水中,摇匀后送LC/MS/MS检测。
实验结果
结果见表3。
表3式(I)化合物对P450同工酶抑制的IC
50值
结果表明:式(I)化合物具有较低的药物-药物相互作用风险。
实验例3:大鼠单次给药后体内药代动力学研究
实验目的
以雄性SD大鼠为受试动物,单次给药后测定化合物血药浓度并评估药代动力学行为。
实验材料:
Sprague Dawley大鼠(雄性,200-300g,7~9周龄,上海维通利华实验动物有限公司)
实验操作:
以标准方案测试待测化合物静脉注射及口服给药后的啮齿类动物药代特征,实验中待测化合物配成澄清溶液或均一混悬液,给予大鼠单次静脉注射及口服给药。静脉注射组溶媒为一定比例的乙醇和生理盐水溶液或一定比例二甲亚砜的HP-β环糊精溶液(调酸至pH=3-4),涡旋搅拌,制备得到1mg/mL澄清溶液,微孔滤膜过滤后备用;口服溶媒为一定比例的羧甲基纤维素钠溶液或一定比例二甲亚砜的HP-β环糊精溶液(调酸至pH=4左右),待测化合物与溶媒混合后,涡旋搅拌,制备得到30mg/mL均一混悬备用。大鼠2mg/kg静脉给药或300mg/kg口服给药后,收集一定量的全血样品,3000g离心15分钟,分离上清得血浆样品,加入3倍体积含内标的乙腈溶液沉淀蛋白,离心取上清液加入2倍体积的水再离心取上清进样,以LC-MS/MS分析方法定量分析血药浓度,并用Phoenix WinNonlin软件(美国Pharsight公司)计算药代参数,如达峰浓度,达峰时间,清除率,半衰期,药时曲线下面积,生物利用度等。
实验结果:
表5式(I)化合物在雄性大鼠体内的药代动力学性质(n=3)
其中,C
0为起始浓度,T
1/2为消除半衰期,Vd
ss为稳态表观分布容积,Cl为总清除率,AUC
0-inf为从0时间到外推至无穷大时的血浆浓度-时间曲线下面积,C
max为达峰浓度,T
max为达峰时间。
结果表明:式(I)化合物具有良好的的大鼠药代动力学性质和口服生物利用度。
实验例4:比格犬单次给药后体内药代动力学研究
实验目的
以雄性比格犬为受试动物,单次给药后测定化合物血药浓度并评估药代动力学行为。
实验材料:
比格犬(雄性,6~12kg,大于6月龄,北京玛斯生物技术公司)
实验操作:
试验目的是测试待测化合物静脉注射及口服给药后的非啮齿类动物药代特征,实验中待测化合物配成澄清溶液或均一混悬液,给予比格犬单次静脉注射或口服给药。静脉注射组溶媒为一定比例二甲亚砜的HP-β-环糊精溶液或一定比例的乙醇,聚乙二醇400和生理盐水溶液,涡旋并超声,制备得到2mg/kg澄清溶液,微孔滤膜过滤后备用;口服溶媒为一定比例二甲亚砜的HP-β
环糊精溶液或一定比例的羧甲基纤维素钠溶液,待测化合物与溶媒混合后,涡旋并超声,制备得到3mg/mL均一混悬液备用。比格犬2mg/kg静脉给药,15mg/kg口服给药后,收集一定量的全血样品,3000g离心10分钟,分离上清得血浆样品,加入10倍体积含内标的乙腈溶液沉淀蛋白,离心取上清液进样,以LC-MS/MS分析方法定量分析血药浓度,并用Phoenix WinNonlin软件(美国Pharsight公司)计算药代参数,如达峰浓度,达峰时间,清除率,半衰期,药时曲线下面积,生物利用度等。
实验结果:
表7式(I)化合物在雄性比格犬体内的药代动力学性质(n=3)
其中,C
0为起始浓度,T
1/2为消除半衰期,Vd
ss为稳态表观分布容积,Cl为总清除率,AUC
0-inf为从0时间到外推至无穷大时的血浆浓度-时间曲线下面积,C
max为达峰浓度,T
max为达峰时间。
结果表明:式(I)化合物具有良好的比格犬药代动力学性质和口服生物利用度。
Claims (20)
- 式(Ⅰ)化合物的制备方法,其包含如下步骤:步骤1:使式SM3-9化合物和式SM3-10化合物反应以获得式SM3-11化合物,步骤2:使式SM1化合物和式1-1化合物反应得到的中间体化合物和式SM2化合物反应以获得式1-2化合物,其中,试剂P选自乙腈;试剂S-1选自乙酸钾;试剂S-2选自三环己基磷、2-二叔丁基膦基-3,4,5,6-四甲基-2,4,6-三异丙基-1,1-联苯、2-(二环己基膦基)-3,6-二甲氧基-2-4-6-三异丙基-1,1-联苯、三苯基磷和2-二环己基磷-2,4,6-三异丙基联苯;催化剂U选自醋酸钯、二苯基磷二茂铁二氯化钯、四三苯基磷钯、烯丙基氯化钯二聚物、肉桂基氯化钯二聚体和三氟乙酸钯;碱T选自碳酸钠、碳酸铯和碳酸钾;溶剂V选自二氧六环、甲基环戊基醚、甲苯、甲基四氢呋喃和四氢呋喃。
- 根据权利要求1所述的制备方法,其包含如下反应路线:其中,试剂A选自2-甲氧基乙胺;溶剂B选自四氢呋喃;试剂C选自乙酰氯;试剂D选自乙酰氯;溶剂E选自乙醇;还原剂F选自四氢铝锂(片状)、硼烷四氢呋喃溶液和硼烷二甲硫醚复合物;溶剂G选自四氢呋喃;试剂H选自磺酸异氰酸酯;试剂I选自叔丁醇;碱J选自三乙胺和二异丙基乙胺;溶剂K选自二氧六环和二氯甲烷;试剂L选自邻苯二甲酰基钾盐、钠氢、叔丁醇钾、叔丁醇钠、碳酸钾和1,8-二氮杂二环十一碳-7-烯/邻苯二甲酰胺;溶剂M选自N,N-二甲基甲酰胺、四氢呋喃、甲醇、二氧六环和二甲基亚砜;试剂N选自水合肼;溶剂O选自乙醇;试剂Q选自对甲苯磺酸、盐酸和三氟乙酸;溶剂R选自四氢呋喃、二氯甲烷和乙酸乙酯;碱W选自吡啶、三乙胺、二异丙基乙胺和碳酸氢钠;溶剂X选自二氯甲烷、N,N-二甲基甲酰胺、四氢呋喃和乙酸乙酯;碱Y选自碳酸钠、二异丙基乙基胺、三乙胺、吡啶、碳酸氢钠、碳酸钾和氢氧化钠;溶剂Z选自四氢呋喃/水、甲基四氢呋喃、二氯甲烷和甲基四氢呋喃/水。
- 根据权利要求1或2所述的制备方法,其中,制备化合物SM3-11的步骤中,控制反应体系温度范围为65±5℃。
- 根据权利要求1或2所述的制备方法,其中,化合物SM3-9与化合物SM3-10的摩尔比为1:1.2~2。
- 根据权利要求1或2所述的制备方法,其中,化合物SM1与催化剂U的摩尔比为1:0.05~0.1。
- 根据权利要求2所述的制备方法,其中,制备化合物SM3-3的步骤中,向反应体系中投料时,控制反应体系温度范围为0±5℃。
- 根据权利要求2所述的制备方法,其中,化合物SM3-3与试剂C的摩尔比为1:12~17。
- 根据权利要求2所述的制备方法,其中,制备化合物SM3-5的步骤中,向反应体系中投料时,控制反应体系温度范围为0±5℃。
- 根据权利要求2所述的制备方法,其中,制备化合物SM3-6的步骤中,化合物SM3-5与还原剂F的摩尔比为1:2~4。
- 根据权利要求2所述的制备方法,其中,制备化合物SM3-7的步骤中,向反应体系中投料时,控制反应体系温度范围为15±5℃。
- 根据权利要求2所述的制备方法,其中,制备化合物SM3-7的步骤中,试剂投料完毕后,控制反应体系温度范围为20±5℃。
- 根据权利要求2所述的制备方法,其中,制备化合物SM3-7的步骤中,反应完成后,保持在氮气环境下过滤。
- 根据权利要求2所述的制备方法,其中,制备化合物SM3-7的步骤中,试剂投料完毕后,控制反应体系温度范围为80±5℃。
- 根据权利要求2所述的制备方法,其中,制备化合物SM3-8的步骤中,后处理用酸调节pH时控制在2.7~3.5。
- 根据权利要求2所述的制备方法,其中,制备化合物SM3-8的步骤中,后处理调节pH时控制反应体系温度范围为35±5℃。
- 根据权利要求2所述的制备方法,其中,化合物SM3-8与试剂N的的摩尔比为1:1.5~2。
- 根据权利要求2所述的制备方法,其中,化合物SM3-11与试剂Q的摩尔比为1:2.5~4。
- 根据权利要求2所述的制备方法,其中,制备化合物1-4的步骤中,向反应体系中投料时,控制反应体系温度为5±5℃。
- 根据权利要求2所述的制备方法,其中,制备化合物1-4的步骤中,试剂投料完毕后,反应时间为1.5±0.5小时。
- 根据权利要求2所述的制备方法,其中,化合物1-4与碱Y的摩尔比为1:5。
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