WO2021172922A1 - 헤테로사이클릭아민 유도체의 제조 방법 - Google Patents
헤테로사이클릭아민 유도체의 제조 방법 Download PDFInfo
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- WO2021172922A1 WO2021172922A1 PCT/KR2021/002440 KR2021002440W WO2021172922A1 WO 2021172922 A1 WO2021172922 A1 WO 2021172922A1 KR 2021002440 W KR2021002440 W KR 2021002440W WO 2021172922 A1 WO2021172922 A1 WO 2021172922A1
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- compound represented
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- manufacturing
- ethyl acetate
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- 238000000034 method Methods 0.000 title claims abstract description 46
- 238000002360 preparation method Methods 0.000 title abstract description 14
- 150000001875 compounds Chemical class 0.000 claims description 208
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 189
- 238000006243 chemical reaction Methods 0.000 claims description 93
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 53
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- 239000000243 solution Substances 0.000 claims description 37
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 30
- 238000002425 crystallisation Methods 0.000 claims description 29
- 230000008025 crystallization Effects 0.000 claims description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 29
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 28
- 238000004519 manufacturing process Methods 0.000 claims description 27
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 26
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 19
- 238000000605 extraction Methods 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 17
- 239000000047 product Substances 0.000 claims description 17
- 239000000706 filtrate Substances 0.000 claims description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 239000000126 substance Substances 0.000 claims description 15
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- 229910052763 palladium Inorganic materials 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 8
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical group [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 claims description 7
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 7
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 235000011181 potassium carbonates Nutrition 0.000 claims description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 claims description 3
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 3
- 229940086066 potassium hydrogencarbonate Drugs 0.000 claims description 3
- 229940043279 diisopropylamine Drugs 0.000 claims description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 2
- CUBIJGNGGJBNOC-UHFFFAOYSA-N palladium;tris(2-methylphenyl)phosphane Chemical compound [Pd].CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C.CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C CUBIJGNGGJBNOC-UHFFFAOYSA-N 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- RWMKSKOZLCXHOK-UHFFFAOYSA-M potassium;butanoate Chemical compound [K+].CCCC([O-])=O RWMKSKOZLCXHOK-UHFFFAOYSA-M 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 23
- 230000008901 benefit Effects 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- 230000008569 process Effects 0.000 description 33
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 30
- 239000010410 layer Substances 0.000 description 24
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- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 10
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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 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Definitions
- the present invention relates to a process for the preparation of heterocyclic amine derivatives.
- Interleukin-2 Tyrosine Kinase (ITK) and Bruton's Tyrosine Kinase (BTK) belong to the TEC family along with tyrosine kinase expressed in hepatocellular carcinoma (Tec), Resting Lymphocyte Kinase (RLK) and BMX (Bone-Marrow tyrosine kinase gene on chromosome X). It is a type of tyrosine kinase that does not have a receptor and acts on various immune responses.
- ITK is expressed not only on T cells but also on NK cells and mast cells, and produces important cytokines such as IL-2, IL-4, IL-5, IL-10, IL-13 and IL-17 and T-cell proliferation.
- T cells are activated by TCR signaling, and activated T cells produce inflammatory cytokines, activate B cells and macrophages to induce autoimmune diseases such as RA (Sahu N. et al. Curr Top Med Chem. 2009, 9, 690).
- RA disease is caused by activation of T cells as Th1 cells, but recently it has been reported that Th1 cells as well as Th17/Treg act as the etiology of RA (J Leipe J. et al. Arthritis Rheum. 2010, 62). , 2876).
- ITK has been previously developed as a target for immunotherapeutic drugs such as asthma, but has not been developed as an RA treatment (Lo H. Y Expert Opin Ther Pat. 2010, 20, 459).
- RA treatment Li H. Y Expert Opin Ther Pat. 2010, 20, 459
- BTK functions as a regulator of early B-cell development as well as mature B-cell activation, signaling and survival.
- a signal is transmitted to the B-cells by a B-cell receptor (BCR) that recognizes an antigen attached to the surface of an antigen-presenting cell, and is activated as a mature antibody-producing cell.
- BCR B-cell receptor
- aberrant signal transduction by BCR leads to abnormal B-cell proliferation and formation of pathological autoantibodies, which may lead to cancer, autoimmune and/or inflammatory diseases.
- signal transduction by BCR may be blocked when BTK is deficient. Accordingly, inhibition of BTK can block B-cell mediated disease processes, so the use of BTK inhibitors may be a useful approach for the treatment of B-cell mediated diseases.
- BTK can also be expressed by other cells that may be associated with disease in addition to B-cells.
- BTK is an important component of Fc-gamma signaling in bone marrow cells, and is expressed by mast cells.
- BTK-deficient bone marrow-derived mast cells exhibit impaired antigen-induced degranulation, and inhibition of BTK activity is known to be useful for treating pathological mast cell responses such as allergy and asthma (Iwaki et al. J. Biol). Chem. 2005 280:40261).
- monocytes from XLA patients without BTK activity have reduced TNF alpha production following stimulation, thereby suppressing TNF alpha-mediated inflammation by BTK inhibitors (Horwood et al. J. Exp. Med. 197: 1603, 2003).
- WO2008/039218 has disclosed a 4-aminopyrazolo[3,4-d]pyrimidinylpiperidine derivative
- WO2015/ 061247 discloses hetero compounds such as pyridine, pyrimidine, pyrazine and pyridazine compounds
- WO2014/055934 discloses pyrimidinylphenylacrylamide derivatives.
- WO2005/066335 discloses aminobenzimidazole
- WO2005/056785 discloses pyridone
- WO2002050071 discloses aminothiazole derivatives
- WO2014/036016 discloses benzimidazole derivatives.
- the present inventors have confirmed that a heterocyclic amine derivative having a different chemical structure from the BTK and ITK inhibitors reported to date can exhibit an excellent effect of inhibiting the dual activity of BTK and ITK. Accordingly, as a result of intensive research on a preparation method capable of preparing a novel heterocyclic amine derivative, when the preparation method described later is used, mass production is possible commercially, and furthermore, the overall yield is improved and impurities are reduced. By confirming the present invention was completed.
- the present invention is to provide a method for preparing a heterocyclic amine derivative.
- the present invention provides a manufacturing method as shown in Scheme 1 below, and more specifically provides a manufacturing method comprising the following steps:
- the compound represented by Formula 1 may be understood as a concept encompassing all of the following three types of compounds according to chirality.
- Step 1 is a step of reacting a compound represented by Formula 1-1 with a compound represented by Formula 1-2 to prepare a compound represented by Formula 1-3, wherein the reaction is an amine substitution reaction. It is carried out in the presence of a palladium catalyst and a base.
- the compound represented by Formula 1-1 and the compound represented by Formula 1-2 may be used in a molar ratio of 1:0.1 to 1:2.
- the compound represented by Formula 1-1 and the compound represented by Formula 1-2 are in a molar ratio of 1:0.5 to 1:1.7, 1:0.7 to 1:1.5, or 1:0.9 to 1:1.5. can be used
- the palladium catalyst may be a palladium (0) catalyst having a valency of 0 of palladium (Pd) in the compound, or a palladium (II) catalyst having a valency of +2.
- a palladium catalyst tris(dibenzylideneacetone)dipalladium(0), tetrakis(triphenylphosphine)palladium(O), bis[tris(2-methylphenyl)phosphine]palladium and palladium(II) ) at least one selected from the group consisting of acetate may be used.
- the base used in the reaction of step 1 may be at least one selected from the group consisting of cesium carbonate, potassium carbonate, sodium carbonate, sodium tert-butoxide and potassium tert-butoxide. Among them, it is preferable to use cesium carbonate in terms of reaction rate and yield.
- the reaction may be performed in the presence of a phosphine-based compound together with the palladium catalyst and the base.
- a phosphine-based compound 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 2-( Dicyclohexylphosphino)-3,6-dimethoxy-2,4'6'-triisopropyl-1,1'-biphenyl and dicyclohexylphosphino-2',6'-diisopropoxybi At least one selected from the group consisting of phenyl may be used.
- a solvent for the reaction a solvent that is inert to the amine substitution reaction may be used.
- solvents such as toluene, dioxane, dimethylformamide (DMF), butyl alcohol, or dimethylacetamide (DMA C ) may be used, but in terms of reaction rate and yield, toluene and dimethylacetamide (DMA C ) desirable.
- the solvent is 10 to 30 times the volume of the compound represented by Formula 1-1 (mL/g), more specifically, 15 to 25 times the volume (mL/g) ) can be used as
- the reaction may be carried out at a temperature of 80 to 150 °C for 3 hours to 15 hours.
- the reaction may not proceed sufficiently, and thus the production yield may be lowered.
- the reaction may be performed at a temperature of 90 to 130° C. for 4 hours to 12 hours, preferably 4 hours to 10 hours, more preferably 6 hours to 10 hours.
- step 1) may be applied as a process for mass production of the compound represented by Formula 1 above.
- steps 1 and 2 to be described later are performed in-situ (In) in the same reaction vessel. -situ) can be done.
- the method for preparing the compound represented by Formula 1 including Step 1 may be advantageous in terms of industrial mass production of the compound.
- Step 2 is a step of reacting the compound represented by Formula 1-3 in the presence of an acid to prepare a compound represented by Formula 1-4, wherein the blood of the compound represented by Formula 1-3 is prepared in the presence of an acid. This is a step of removing the tert-butyloxycarbonyl group, which is a protecting group substituted on the peridine ring.
- hydrochloric acid As the acid used in the reaction of step 2), hydrochloric acid, acetic acid, trichloroacetic acid, or trifluoroacetic acid may be used. Among them, hydrochloric acid is preferably used in consideration of yield and cost.
- a solvent for the reaction a solvent such as ethyl acetate, methyl alcohol, dioxane, or toluene may be used.
- the reaction may be performed at room temperature for 30 minutes to 20 hours, preferably 30 minutes to 4 hours.
- Removal of the tert-butyloxycarbonyl group, which is a protecting group corresponds to a reaction that occurs easily without additional heat treatment and may be performed at room temperature.
- the reaction time is less than 30 minutes, the reaction may not proceed sufficiently, and when the reaction time exceeds 20 hours, the production yield does not substantially increase, so the above-described reaction time is preferable.
- step 2 a crystallized compound represented by Formula 1-4 is prepared by using a crystallization solvent in the product of the reaction.
- step 2) may be performed by reacting the compound represented by Formula 1-3 in the presence of an acid and then crystallizing the product of the reaction to prepare the compound represented by Formula 1-4.
- the crystallization step may be performed by primary crystallization with water and secondary crystallization with methanol.
- the product of the reaction generated after the completion of the reaction in step 2) is sequentially crystallized with water and methanol, the palladium catalyst, ligand, aminothiazole residue, etc., which are by-products remaining after the reaction, can be effectively removed. have. Accordingly, a compound of high purity can be obtained in high yield compared to the process of purification in the form of a slurry using a solvent such as ethyl acetate.
- the primary crystallization process with water may be performed by adding water to the product of the reaction and stirring at a temperature of about 0 to 5° C. for 10 minutes to 2 hours.
- the crystallization is preferably performed in the presence of a base such as sodium hydroxide while maintaining the pH of the reactant at 11 or more, or 12 or more.
- a base such as sodium hydroxide
- the reaction solution is filtered under reduced pressure after completion of the reaction to obtain crystals.
- the water is in an amount of 5 to 30 times the volume of the compound represented by Formula 1-1 (mL/g), more specifically, in an amount of 5 to 25 times the volume (mL/g). ) can be used as
- a secondary crystallization process with methanol may be performed.
- the secondary crystallization process using methanol may be performed by adding methanol to the obtained crystals and stirring at a temperature of about 50 to 80° C. for 10 minutes to 2 hours.
- the methanol is 5 to 40 times the volume of the compound represented by Formula 1-1 (mL/g), more specifically, 10 to 35 times the volume (mL/g) ) can be used as
- Step 3 is a step of preparing the compound represented by Formula 1 by reacting the compound represented by Formula 1-4 with the compound represented by Formula 1-5.
- the reaction is preferably performed in the presence of a base as an amidation reaction.
- the compound represented by Formula 1-4 and the compound represented by Formula 1-5 may be used in a molar ratio of 1:0.5 to 1:2.0. Specifically, the compound represented by Formula 1-4 and the compound represented by Formula 1-5 are in a molar ratio of 1:0.5 to 1:1.5, 1:0.7 to 1:1.3, or 1:0.9 to 1:1.1. can be used
- Examples of the base used in the reaction of step 3 include potassium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, diisopropylamine, diisopropylethylamine, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium carbonate, At least one selected from the group consisting of sodium carbonate, sodium methylate and potassium butyrate may be used. Among them, it is preferable to use potassium carbonate, sodium carbonate, sodium hydrogen carbonate, or potassium hydrogen carbonate from the viewpoint of completion of the reaction and generation of by-products.
- a mixed solvent of tetrahydrofuran (THF) and water may be used.
- the tetrahydrofuran may be used in an amount (mL/g) of 10 to 40 times the weight of the compound represented by Formula 1-4
- the water is the compound represented by Formula 1-4 It can be used in an amount (mL/g) of 2 to 10 times the volume of the weight.
- the compound represented by Formula 1-5 may be added in a mixed state with N,N-diisopropylethylamine or triethylamine.
- the compound represented by Formula 1-5 acryloyl chloride, a small amount of hydrochloric acid remaining in the compound is present. Accordingly, the hydrochloric acid participates in the reaction, and as a by-product, impurities such as a compound in which HCl is added to a double bond of the compound represented by Formula 1 and a compound in which HCl is added to a double bond of acrylamide (hereinafter, impurity C (ImpC)) ) to produce, there was a problem of reducing the purity of the final compound.
- impurity C impurity C
- N N,N-diisopropylethylamine
- DIPEA N,N-diisopropylethylamine
- the N,N-diisopropylethylamine is compared to 1 mole of the compound represented by Formula 1-5 It may be included in 0.01 to 0.2 mole. Within the above range, hydrochloric acid in the compound represented by Formula 1-5 may be effectively removed.
- the reaction may be carried out at a temperature of -10 °C to 10 °C, preferably at a temperature of 0 °C or less, more preferably at a temperature of -10 °C or more and less than 0 °C.
- a dimer (hereinafter, impurity B (ImpB)) of the compound represented by Formula 1 may be prepared by the reaction, and generation of such impurity B may be minimized when the reaction proceeds at a low temperature.
- a reaction temperature of -10 to 0° C. more specifically, a reaction temperature of -8 to -3° C., is preferable in terms of impurity reduction and production yield. Accordingly, it is preferable to use the reactants and organic solvents used after cooling to a temperature of 0° C. or less, which are used to suppress the increase in the reaction temperature during the reaction.
- the compound represented by Formula 1 may be isolated and purified, if necessary, including at least one of extraction, purification by vacuum concentration, and crystallization of the reaction product. In order to prepare a compound of high purity, it is preferable to sequentially perform all of the steps of extracting, purifying, and crystallizing the reaction product.
- the step of extracting the product of the reaction using ethyl acetate may be further included.
- the product of the reaction may be extracted using ethyl acetate and water. That is, the compound represented by Formula 1 may be extracted using ethyl acetate and water after completion of the reaction.
- impurities having a relative retention time of less than 1.0 separated by high-performance liquid chromatography (HPLC) are removed. It can be effectively removed with a layer of water.
- the extraction step with ethyl acetate may be performed at a pH of 6.5 to 7.5.
- the pH is lower than 6.5, there is a risk of a decrease in yield, and when the pH is higher than 7.5, it may be difficult to remove impurities.
- the extraction process with ethyl acetate may be carried out in the range of pH 7.0 to 7.5.
- the step 3 dissolving the product of the reaction in tetrahydrofuran; mixing a solution containing phosphoric acid with the prepared solution; And it may further include a purification step of filtering the prepared mixture and then concentrating the filtrate under reduced pressure.
- This vacuum concentration step is preferably performed after the extraction process with ethyl acetate.
- the purification step may include dissolving the product extracted with ethyl acetate in tetrahydrofuran to prepare a solution; mixing a solution containing phosphoric acid with the solution to prepare a mixture in which a phosphate salt is produced; and filtering the mixture in which the phosphate is produced and then concentrating the filtrate under reduced pressure.
- the phosphoric acid-containing solution phosphoric acid is dissolved in a tetrahydrofuran solvent, and in this case, the phosphoric acid may be dissolved in an amount of 0.05 to 0.5 moles relative to 1 mole of the compound represented by Formula 1-4.
- the compound represented by Formula 1 and the compound represented by Formula 1-4 are combined (hereinafter, Impurity A (ImpA)) reacts with a phosphate anion (PO 4 3- ) to produce a phosphate, and the produced phosphate can be easily removed by filtration. content may be lowered.
- step 3 may further include crystallizing the product of the reaction with ethyl acetate. This crystallization step is preferably performed after the purification process.
- the crystallization step may be performed by adding ethyl acetate to the product concentrated under reduced pressure after the purification process and stirring at a temperature of about 20 to 40° C. for 30 minutes to 4 hours.
- the reaction solution is dried under reduced pressure after completion of the reaction to obtain a final product, a compound represented by Chemical Formula 1-1.
- Step 3 may proceed as follows:
- the production method according to the present invention has the advantage that a heterocyclic amine derivative having a reduced impurity content can be prepared in high yield.
- 2,6-dichloroisonicotinic acid (10.0 g, 1.0 eq) was dissolved in dimethylformamide (100.0 mL), and 1,1-carbonyldiimidazole (1.0 g, 1.2 eq) was added thereto. After stirring at room temperature (25-30 °C) for 1 hour under nitrogen gas, morpholine (5.4 mL, 1.2 eq) was added thereto, followed by stirring at the same temperature for 2 hours to complete the reaction. Ethyl acetate (200.0 mL) and water (200.0 mL) were added for extraction, and the aqueous layer was re-extracted three times using ethyl acetate (200.0 mL).
- step a The compound represented by Formula 1-a (10.0 g, 1.0 eq) obtained in step a was dissolved in dichloromethane (100.0 mL), and then cooled to 0 to 10 °C under nitrogen gas.
- 1M borane-tetrahydrofuran 115.0 mL, 3.0 eq
- 6N-hydrochloric acid aqueous solution 256.0 mL, 20.0 eq
- step b After dissolving the compound of formula 1-b obtained in step b (1.0 g, 1.0 eq) in 1,4-dioxane (10.0 mL), tris(dibenzylideneacetone)dipalladium(0)(465.8 mg) , 0.2 eq) and xanphos (1.5 g, 0.4 eq) were added.
- the compound represented by Formula 1-1 (50.0 g, 1.0 eq), the compound represented by Formula 1-2 (16.7 g, 1.2 eq), and tris(dibenzylideneacetone)dipalladium obtained in Preparation Example in a flask (0) (11.1 g, 0.1 eq), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; BINAP) (30.3 g, 0.4 eq), cesium carbonate (118.9 g, 3.0 eq), and 1000 mL of toluene 20 times the weight of the compound represented by Formula 1-1 were added and stirred at room temperature for 10 minutes.
- the reaction was completed by stirring at a temperature range of 105 to 111 °C for 8 hours.
- the catalyst and the formed inorganic salt were removed from the obtained residue through celite filtration.
- the organic layer was concentrated under reduced pressure, 250 mL of purified water in a volume 5 times the weight of the compound represented by Formula 1-1, and ethyl acetic acid in a volume 20 times the weight of the compound represented by Formula 1-1 1000 mL was added to extract the organic layer.
- the aqueous layer generated here was discarded.
- the organic layer was concentrated under reduced pressure at 40-45° C. to prepare a compound represented by Chemical Formula 1-3, which was used subsequent to step 2 without further purification.
- EA Ethyl acetate
- 6N-HCl 250 mL, 5.0 eq
- the aqueous layer was extracted, and 1000 mL of purified water (20 times the volume of the compound represented by Formula 1-1 (mL/g)) was added to the organic layer for secondary extraction.
- 1000 mL of purified water (20 times the volume of the compound represented by Formula 1-1 (mL/g)) was added to the organic layer for secondary extraction.
- N,N-diisopropylethylamine N,N-Diisopropylethylamine; DIPEA
- DIPEA diisopropylethylamine
- the formula 1-5 in 5 mL of THF cooled to -8 to -3 ° C.
- a solution of the compound (1.1 mL, 1.05 eq) was added dropwise at an internal temperature of -8 to -3°C. This was stirred at -8 to -3 °C for 0.5 hours to complete the reaction.
- the compound represented by Formula 1-3 (500.0 mg, 1.0 eq) obtained in Step 1 was dissolved in dichloromethane (10.0 mL), and then cooled to 0-10°C.
- trichloroacetic acid (1.6 mL, 20.0 eq) was slowly added dropwise, followed by stirring for 1 hour.
- the separated dichloromethane layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure.
- ethyl artesate (10.0 mL) was added to form crystals for 30 minutes.
- the resulting crystals were filtered and dried to obtain 357.5 mg of the compound represented by Formula 1-4 (yield: 90.0%).
- the compound represented by Formula 1-4 obtained in step 2 (350.0 mg, 1.0 eq) was dissolved in tetrahydrofuran (7.0 mL), water (7.0 mL) was added, and sodium bicarbonate (226.8 mg, 3.0 eq) was added. After addition, it was cooled to 0-10 °C.
- the compound represented by Formula 1-4 obtained in step 2 (350.0 mg, 1.0 eq) was dissolved in tetrahydrofuran (7.0 mL), water (7.0 mL) was added, and sodium bicarbonate (226.8 mg, 3.0 eq) was added. After addition, it was cooled to 0-10 °C.
- the compound represented by Formula 1-5 (73.1 ⁇ l. 1.0 eq) was slowly added dropwise, followed by stirring for 30 minutes to complete the reaction. This was layer-separated using dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
- Ethyl acetate was added to the obtained residue in an amount (mL/g) 20 times the weight of the residue, followed by stirring at room temperature for 3 hours to form crystals. After filtration, the resulting crystals were dried under reduced pressure at room temperature, and dimethoxyethane was added thereto in an amount (mL/g) 15 times the weight of the crystals, dissolved under reflux, cooled slowly to room temperature, and stirred for 2 hours to form crystals. After filtration, it was dried under reduced pressure at room temperature to obtain 0.12 g of the compound represented by Formula 1 as the 6th material (yield 30.0%).
- Ethyl acetate 5760.0 mL (amount of 20 times the volume of the compound represented by Formula 1-4 (mL/g)) and H 2 O 2880.0 mL (a volume of 10 times the weight of the compound represented by Formula 1-4) (mL/g)) was added, the pH was adjusted to 7.0-7.5 with 1N-HCl solution, and then the layers were separated twice. The separated organic layers were collected and dried over Na 2 SO 4 , and then concentrated under reduced pressure at an external temperature of 40°C.
- THF 5184.0 mL (the amount of 18 times the volume of the compound represented by Formula 1-4 (mL/g) relative to the weight of the compound) was added thereto and dissolved. Thereafter, a solution of H 3 PO 4 (6.8 g, 0.095 eq) in 288.0 mL of THF was added dropwise, followed by stirring for 30 minutes. After removing salts by filtration with Celite, a solution of H 3 PO 4 (6.1 g, 0.085 eq) dissolved in THF 288.0 mL was added dropwise to the filtrate, followed by stirring for 30 minutes. The obtained residue was filtered through Celite to remove salt, and then concentrated under reduced pressure at an external temperature of 40°C.
- N,N-diisopropylethylamine N,N-Diisopropylethylamine; DIPEA
- DIPEA diisopropylethylamine
- the inhibitory activity against BTK and ITK of the compound represented by Formula 1 prepared in the above Example was measured as follows.
- Inhibitory activity evaluation for BTK was evaluated using Promega's 'ADP-GloTM + BTK Kinase enzyme system' kit.
- 10 ⁇ l of BTK enzyme prepared to have a final concentration of 10 ng/ml and a final concentration of 1 uM for a single concentration evaluation of a compound, 1000, 200, 40, 8, 1.6, 0.32 for an IC 50 evaluation
- 5 ⁇ l of nM concentration of the compound was mixed and reacted at room temperature for 15 minutes.
- 5 ⁇ l of substrate and 5 ⁇ l of ATP prepared to have a final concentration of 10 uM were added to the reaction plate, and then reacted at 30° C. for 1 hour.
- ITK Kinase enzyme system' kit 10 ⁇ l of the ITK enzyme prepared to have a final concentration of 4 ng/ml and a final concentration of 1 uM for single concentration evaluation and 1000, 200, 40, 8, 1.6, 0.32 nM for IC 50 evaluation 5 ⁇ l of the compound was mixed and reacted at room temperature for 15 minutes. 5 ⁇ l of substrate and 5 ⁇ l of ATP prepared to a final concentration of 25 uM were added to the reaction plate, and then reacted at 30° C. for 1 hour.
- the inhibitory activity (BTK IC 50 ) of the compound represented by Formula 1 prepared in Examples was 0.4 nM to 1.4 nM, and the inhibitory activity to ITK (ITK IC 50 ) was 1.0 nM to 1.7 nM . Accordingly, it can be confirmed that the compound represented by Formula 1 exhibits an excellent effect of inhibiting the dual activity of BTK and ITK.
- Impurity A having an RRT of 1.17 (ImpA): a compound represented by Formula 1 and a compound represented by Formula 1-4 combined)
- Impurity B having an RRT of 1.37 (ImpB): a dimer of the compound represented by Formula 1
- Impurity C having an RRT of 1.18 a compound in which HCl is added to a double bond of the compound represented by Formula 1, and a compound in which HCl is added to a double bond of acrylamide
- Step 1 & 2 Step 3 total yield final purity transference number water transference number water
- Reference Example 1 58.5% - 60.0% 98.00% 35.1% 98.00%
- Reference Example 2 58.5% - 30.0% 98.00% 17.6% 98.00%
- step 1 And Step 2 is made in-situ, and separation and purification of the compound are performed through crystallization, which is advantageous for industrial production, and it is confirmed that there is no decrease in yield compared to the process of Reference Example 1.
- Example 1 in order to increase the final purity of the compound, compared to the process of Reference Example 2, in which the separation and purification of the compound by primary and secondary crystallization after the process of Reference Example 1 is additionally performed, the final yield is significantly higher. It can be seen that compounds can be prepared.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
column | Capcell Pak C18, 250 x 4.6 mm, 5 ㎛ |
Mobile phase A | 20 mM Ammonium acetate |
Mobile phase B | 100 % Acetonitrile |
UV | 280 nm |
column temp. | 30℃ |
Flaw rate | 1 ml/min |
Sample preparation | 화학식 1로 표시되는 화합물 10 mg / MeOH 25ml |
Gradient |
|
단계 3
수율 |
순도 | RRT<1.0 | ImpA | ImpB | ImpC | |
실시예 | 60% | 99.74% | < 0.1% | < 0.1% | < 0.1% | 0% |
참조예 2 | 30% | 98.00% | 0.5% | 0.5% | - | 0.4% |
참조예 3 | 35% | 98.00% | < 0.1% | 0.6% | 0.13% | 0.08% |
참조예 4 | 60% | 99.00% | < 0.1% | < 0.1% | 0.30% | 0.50% |
참조예 5 | 60% | 99.39% | < 0.1% | < 0.1% | 0.30% | 0% |
단계 1 & 2 | 단계 3 | 총수율 | 최종순도 | |||
수율 | 순도 | 수율 | 순도 | |||
실시예 | 60.3% | 99.8% | 60.0% | 99.74% | 36.0% | 99.74% |
참조예 1 | 58.5% | - | 60.0% | 98.00% | 35.1% | 98.00% |
참조예 2 | 58.5% | - | 30.0% | 98.00% | 17.6% | 98.00% |
Claims (17)
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MX2022010391A MX2022010391A (es) | 2020-02-26 | 2021-02-26 | Metodo de preparacion de derivados de amina heterociclica. |
JOP/2022/0199A JOP20220199A1 (ar) | 2020-02-26 | 2021-02-26 | طريقة لتحضير مشتقات أمين حلقي غير متجانس |
BR112022016729A BR112022016729A2 (pt) | 2020-02-26 | 2021-02-26 | Método para preparação de derivados de heterociclicamina |
JP2022551582A JP7447291B2 (ja) | 2020-02-26 | 2021-02-26 | ヘテロサイクリックアミン誘導体の製造方法 |
CN202180015867.2A CN115151537A (zh) | 2020-02-26 | 2021-02-26 | 制备杂环胺衍生物的方法 |
EP21761001.3A EP4112617A4 (en) | 2020-02-26 | 2021-02-26 | PROCESS FOR PREPARING HETEROCYCLIC AMINE DERIVATIVES |
US17/799,774 US20230094404A1 (en) | 2020-02-26 | 2021-02-26 | Method for preparation of heterocyclicamine derivatives |
CONC2022/0011593A CO2022011593A2 (es) | 2020-02-26 | 2022-08-17 | Método de preparación de derivados de amina heterocíclica |
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Citations (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002050071A1 (en) | 2000-12-21 | 2002-06-27 | Bristol-Myers Squibb Company | Thiazolyl inhibitors of tec family tyrosine kinases |
WO2005056785A2 (en) | 2003-12-05 | 2005-06-23 | Vertex Pharmaceuticals, Inc. | Crystal structure of interleukin-2 tyrosine kinase (itk) and binding pockets thereof |
WO2005066335A1 (en) | 2003-12-30 | 2005-07-21 | Boehringer Ingelheim Pharmaceuticals, Inc. | Crystal structure of the interleukin-2-inducible cell kinase (itk) kinase domain |
WO2008039218A2 (en) | 2006-09-22 | 2008-04-03 | Pharmacyclics, Inc. | Inhibitors of bruton's tyrosine kinase |
WO2012035055A1 (en) * | 2010-09-17 | 2012-03-22 | Glaxo Group Limited | Novel compounds |
WO2014036016A1 (en) | 2012-08-31 | 2014-03-06 | Principia Biopharma Inc. | Benzimidazole derivatives as itk inhibitors |
WO2014055934A2 (en) | 2012-10-04 | 2014-04-10 | University Of Utah Research Foundation | Substituted n-(3-(pyrimidin-4-yl)phenyl)acrylamide analogs as tyrosine receptor kinase btk inhibitors |
WO2015061247A2 (en) | 2013-10-21 | 2015-04-30 | Merck Patent Gmbh | Heteroaryl compounds as btk inhibitors and uses thereof |
CN104628657A (zh) * | 2013-11-06 | 2015-05-20 | 韩冰 | 一类治疗缺血性脑损伤的化合物及其用途 |
US20170233411A1 (en) * | 2014-10-22 | 2017-08-17 | Dana-Farber Cancer Institute, Inc. | Thiazolyl-containing compounds for treating proliferative diseases |
KR20190040773A (ko) * | 2017-10-11 | 2019-04-19 | 주식회사 대웅제약 | 신규한 페닐피리딘 유도체 및 이를 포함하는 약학 조성물 |
KR20200024111A (ko) * | 2018-08-27 | 2020-03-06 | 주식회사 대웅제약 | 신규한 헤테로사이클릭아민 유도체 및 이를 포함하는 약학 조성물 |
-
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- 2021-02-26 CN CN202180015867.2A patent/CN115151537A/zh active Pending
- 2021-02-26 WO PCT/KR2021/002440 patent/WO2021172922A1/ko active Application Filing
- 2021-02-26 US US17/799,774 patent/US20230094404A1/en active Pending
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-
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- 2022-08-17 CO CONC2022/0011593A patent/CO2022011593A2/es unknown
Patent Citations (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002050071A1 (en) | 2000-12-21 | 2002-06-27 | Bristol-Myers Squibb Company | Thiazolyl inhibitors of tec family tyrosine kinases |
WO2005056785A2 (en) | 2003-12-05 | 2005-06-23 | Vertex Pharmaceuticals, Inc. | Crystal structure of interleukin-2 tyrosine kinase (itk) and binding pockets thereof |
WO2005066335A1 (en) | 2003-12-30 | 2005-07-21 | Boehringer Ingelheim Pharmaceuticals, Inc. | Crystal structure of the interleukin-2-inducible cell kinase (itk) kinase domain |
WO2008039218A2 (en) | 2006-09-22 | 2008-04-03 | Pharmacyclics, Inc. | Inhibitors of bruton's tyrosine kinase |
WO2012035055A1 (en) * | 2010-09-17 | 2012-03-22 | Glaxo Group Limited | Novel compounds |
WO2014036016A1 (en) | 2012-08-31 | 2014-03-06 | Principia Biopharma Inc. | Benzimidazole derivatives as itk inhibitors |
WO2014055934A2 (en) | 2012-10-04 | 2014-04-10 | University Of Utah Research Foundation | Substituted n-(3-(pyrimidin-4-yl)phenyl)acrylamide analogs as tyrosine receptor kinase btk inhibitors |
WO2015061247A2 (en) | 2013-10-21 | 2015-04-30 | Merck Patent Gmbh | Heteroaryl compounds as btk inhibitors and uses thereof |
CN104628657A (zh) * | 2013-11-06 | 2015-05-20 | 韩冰 | 一类治疗缺血性脑损伤的化合物及其用途 |
US20170233411A1 (en) * | 2014-10-22 | 2017-08-17 | Dana-Farber Cancer Institute, Inc. | Thiazolyl-containing compounds for treating proliferative diseases |
KR20190040773A (ko) * | 2017-10-11 | 2019-04-19 | 주식회사 대웅제약 | 신규한 페닐피리딘 유도체 및 이를 포함하는 약학 조성물 |
KR20200024111A (ko) * | 2018-08-27 | 2020-03-06 | 주식회사 대웅제약 | 신규한 헤테로사이클릭아민 유도체 및 이를 포함하는 약학 조성물 |
Non-Patent Citations (11)
Title |
---|
FOWELL ET AL., IMMUNITY, vol. 11, 1999, pages 399 |
GOMEZ-RODRIGUEZ J ET AL., J. EXP. MED., vol. 211, 2014, pages 529 |
HARLING JOHN D., DEAKIN ANGELA M., CAMPOS SÉBASTIEN, GRIMLEY RACHEL, CHAUDRY LAIQ, NYE CATHERINE, POLYAKOVA OXANA, BESSANT CHRISTI: "Discovery of Novel Irreversible Inhibitors of Interleukin (IL)-2-inducible Tyrosine Kinase (Itk) by Targeting Cysteine 442 in the ATP Pocket", JOURNAL OF BIOLOGICAL CHEMISTRY, AMERICAN SOCIETY FOR BIOCHEMISTRY AND MOLECULAR BIOLOGY, US, vol. 288, no. 39, 9 August 2013 (2013-08-09), US, pages 28195 - 28206, XP055841724, ISSN: 0021-9258, DOI: 10.1074/jbc.M113.474114 * |
HORWOOD ET AL., J. EXP. MED., vol. 197, 2003, pages 1603 |
IWAKI ET AL., J. BIOL CHEM. |
J LEIPE J ET AL., ARTHRITIS RHEUM., vol. 62, 2010, pages 2876 |
LO H. Y, EXPERT OPIN THER PAT., vol. 20, 2010, pages 459 |
SAHU N. ET AL., CURR TOP MED CHEM., vol. 9, 2009, pages 690 |
SCHAEFFER ET AL., NAT. IMMUNE, vol. 2, 2001, pages 1183 |
See also references of EP4112617A4 |
ZHONG Y. ET AL., THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 290, 2015, pages 5960 |
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CN115151537A (zh) | 2022-10-04 |
JP2023515197A (ja) | 2023-04-12 |
EP4112617A1 (en) | 2023-01-04 |
BR112022016729A2 (pt) | 2022-10-11 |
CO2022011593A2 (es) | 2022-08-30 |
US20230094404A1 (en) | 2023-03-30 |
EP4112617A4 (en) | 2024-03-13 |
JOP20220199A1 (ar) | 2023-01-30 |
JP7447291B2 (ja) | 2024-03-11 |
MX2022010391A (es) | 2022-09-05 |
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