CN114409629A - Preparation method and application of high-purity Relugolix key intermediate - Google Patents
Preparation method and application of high-purity Relugolix key intermediate Download PDFInfo
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- CN114409629A CN114409629A CN202210162521.1A CN202210162521A CN114409629A CN 114409629 A CN114409629 A CN 114409629A CN 202210162521 A CN202210162521 A CN 202210162521A CN 114409629 A CN114409629 A CN 114409629A
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- palladium
- relugolix
- purity
- key intermediate
- salt
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- AOMXMOCNKJTRQP-UHFFFAOYSA-N 1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea Chemical compound C1=CC(NC(=O)NOC)=CC=C1C1=C(CN(C)C)C(C(=O)N(C=2N=NC(OC)=CC=2)C(=O)N2CC=3C(=CC=CC=3F)F)=C2S1 AOMXMOCNKJTRQP-UHFFFAOYSA-N 0.000 title claims abstract description 28
- 229950004238 relugolix Drugs 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 31
- 239000003054 catalyst Substances 0.000 claims abstract description 25
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 15
- 239000002028 Biomass Substances 0.000 claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 10
- -1 (2, 6-difluorobenzyl) (ethoxycarbonyl) amino Chemical group 0.000 claims abstract description 9
- DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 claims abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- 238000003756 stirring Methods 0.000 claims description 20
- 239000007787 solid Substances 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 12
- 239000012535 impurity Substances 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 11
- 229920001661 Chitosan Polymers 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 10
- 238000005406 washing Methods 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- 229910052751 metal Inorganic materials 0.000 claims description 9
- 239000002184 metal Substances 0.000 claims description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 8
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 8
- 150000002940 palladium Chemical class 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- MQRWBMAEBQOWAF-UHFFFAOYSA-N acetic acid;nickel Chemical compound [Ni].CC(O)=O.CC(O)=O MQRWBMAEBQOWAF-UHFFFAOYSA-N 0.000 claims description 7
- 229940078494 nickel acetate Drugs 0.000 claims description 7
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 claims description 6
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 6
- 229940126062 Compound A Drugs 0.000 claims description 5
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 238000001027 hydrothermal synthesis Methods 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 229910052573 porcelain Inorganic materials 0.000 claims description 5
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- 150000001868 cobalt Chemical class 0.000 claims description 4
- 150000001879 copper Chemical class 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical group [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 3
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N alpha-methyl toluene Natural products CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 claims description 3
- 239000012298 atmosphere Substances 0.000 claims description 3
- 239000012065 filter cake Substances 0.000 claims description 3
- 150000002815 nickel Chemical class 0.000 claims description 3
- 238000001291 vacuum drying Methods 0.000 claims description 3
- 229910021503 Cobalt(II) hydroxide Inorganic materials 0.000 claims description 2
- 229910021594 Copper(II) fluoride Inorganic materials 0.000 claims description 2
- 229910021585 Nickel(II) bromide Inorganic materials 0.000 claims description 2
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 claims description 2
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 claims description 2
- 229940011182 cobalt acetate Drugs 0.000 claims description 2
- GVPFVAHMJGGAJG-UHFFFAOYSA-L cobalt dichloride Chemical compound [Cl-].[Cl-].[Co+2] GVPFVAHMJGGAJG-UHFFFAOYSA-L 0.000 claims description 2
- QAHREYKOYSIQPH-UHFFFAOYSA-L cobalt(II) acetate Chemical compound [Co+2].CC([O-])=O.CC([O-])=O QAHREYKOYSIQPH-UHFFFAOYSA-L 0.000 claims description 2
- BZRRQSJJPUGBAA-UHFFFAOYSA-L cobalt(ii) bromide Chemical compound Br[Co]Br BZRRQSJJPUGBAA-UHFFFAOYSA-L 0.000 claims description 2
- ASKVAEGIVYSGNY-UHFFFAOYSA-L cobalt(ii) hydroxide Chemical compound [OH-].[OH-].[Co+2] ASKVAEGIVYSGNY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000365 copper sulfate Inorganic materials 0.000 claims description 2
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 2
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 2
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 2
- GWFAVIIMQDUCRA-UHFFFAOYSA-L copper(ii) fluoride Chemical compound [F-].[F-].[Cu+2] GWFAVIIMQDUCRA-UHFFFAOYSA-L 0.000 claims description 2
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 238000011010 flushing procedure Methods 0.000 claims description 2
- 239000007789 gas Substances 0.000 claims description 2
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 claims description 2
- IPLJNQFXJUCRNH-UHFFFAOYSA-L nickel(2+);dibromide Chemical compound [Ni+2].[Br-].[Br-] IPLJNQFXJUCRNH-UHFFFAOYSA-L 0.000 claims description 2
- BFDHFSHZJLFAMC-UHFFFAOYSA-L nickel(ii) hydroxide Chemical compound [OH-].[OH-].[Ni+2] BFDHFSHZJLFAMC-UHFFFAOYSA-L 0.000 claims description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 2
- INIOZDBICVTGEO-UHFFFAOYSA-L palladium(ii) bromide Chemical compound Br[Pd]Br INIOZDBICVTGEO-UHFFFAOYSA-L 0.000 claims description 2
- GPNDARIEYHPYAY-UHFFFAOYSA-N palladium(ii) nitrate Chemical compound [Pd+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O GPNDARIEYHPYAY-UHFFFAOYSA-N 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 238000000034 method Methods 0.000 claims 6
- 230000000694 effects Effects 0.000 abstract description 3
- 238000005516 engineering process Methods 0.000 abstract description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 abstract description 2
- 239000006185 dispersion Substances 0.000 abstract description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 15
- 238000006115 defluorination reaction Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 6
- 239000013078 crystal Substances 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 4
- 238000002386 leaching Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000000579 Gonadotropin-Releasing Hormone Substances 0.000 description 3
- 101000857870 Squalus acanthias Gonadoliberin Proteins 0.000 description 3
- XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-AQJXLSMYSA-N 0.000 description 3
- 229940035638 gonadotropin-releasing hormone Drugs 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 206010067269 Uterine fibrosis Diseases 0.000 description 2
- 206010046798 Uterine leiomyoma Diseases 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 201000010260 leiomyoma Diseases 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- QDHHCQZDFGDHMP-UHFFFAOYSA-N Chloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 201000009273 Endometriosis Diseases 0.000 description 1
- 108010000817 Leuprolide Proteins 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000002474 gonadorelin antagonist Substances 0.000 description 1
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 1
- 229960004338 leuprorelin Drugs 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 208000007106 menorrhagia Diseases 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
- B01J23/70—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of the iron group metals or copper
- B01J23/89—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of the iron group metals or copper combined with noble metals
- B01J23/892—Nickel and noble metals
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J37/00—Processes, in general, for preparing catalysts; Processes, in general, for activation of catalysts
- B01J37/08—Heat treatment
- B01J37/082—Decomposition and pyrolysis
- B01J37/084—Decomposition of carbon-containing compounds into carbon
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J37/00—Processes, in general, for preparing catalysts; Processes, in general, for activation of catalysts
- B01J37/08—Heat treatment
- B01J37/10—Heat treatment in the presence of water, e.g. steam
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Physics & Mathematics (AREA)
- Thermal Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method and application of a high-purity Relugolix key intermediate, wherein an environment-friendly palladium-based bimetallic biomass supported catalyst is prepared, a high-efficiency catalytic hydrogenation technology is developed, and a high-purity Rulugol key intermediate 2- ((2, 6-difluorobenzyl) (ethoxycarbonyl) amino) -4- ((dimethylamino) methyl) -5- (4-aminophenyl) thiophene-3-formate compound and dihydrochloride thereof are developed and prepared. The invention has the advantages of high catalyst activity, good stability, high active component dispersion degree, long service life, repeated use, short flow, simple operation, easy control of reaction, simple equipment requirement and the like; the prepared Relugolix key intermediate has high purity and good stability.
Description
Technical Field
The invention belongs to the technical field of organic synthesis and preparation of raw material medicines, and particularly relates to a preparation method and application of a high-purity Relugolix key intermediate.
Background
The chemical name of relugori (Relugolix) is: n- [4- [1- [ (2, 6-difluorophenyl) methyl ] -5- [ (dimethylamino) methyl ] -1,2,3, 4-tetrahydro-3- (6-methoxy-3-pyridazinyl) -2, 4-dioxothieno [2,3-D ] pyrimidin-6-yl ] phenyl ] -N' -methoxyurea, which is a gonadotropin releasing hormone antagonist (GnRH) developed by Wuta corporation of Japan and marketed in Japan in 2018, is a small molecule gonadotropin releasing hormone (GnRH) receptor antagonist, and has potential for indications such as uterine fibroids, endometriosis, prostate cancer and the like.
The chemical structure is as follows:
wutian medicine compares the safety and effectiveness of Relugolix and leuprorelin in treating menorrhagia uterine fibrosis and the safety and effectiveness of the two drugs in treating pain symptoms associated with uterine fibrosis through a series of phase III clinical studies conducted in Japan, and finally confirms the safety and effectiveness of Relugolix for uterine fibroids. With the increasing sales, the demand of the bulk drug rilogeli is also increasing, and thus the requirements for the bulk drug preparation process are higher and higher. The prior Ruogeli preparation process still has a series of problems of long route, high cost, unfriendly environment, unstable quality and the like. Therefore, there is a real need for optimizing and improving the preparation process of Ruogeli.
Chinese patent CN 112745304 a discloses a preparation method of Relugolix and an intermediate compound, wherein a palladium metal catalyst is used in the preparation method of a Relugolix (Relugolix) key intermediate 2- ((2, 6-difluorobenzyl) (ethoxycarbonyl) amino) -4- ((dimethylamino) methyl) -5- (4-aminophenyl) thiophene-3-carboxylate compound, and the synthetic route is as follows:
the prior art mainly has the following problems: 1) the use amount of the used palladium catalyst is large (5-10%), the production cost is increased along with the rise of the price of metal palladium, and the product is easy to blacken in hydrogenation, so that the treatment difficulty is increased, and the metal palladium residue is caused; 2) defluorination impurities which are difficult to remove are easily generated during hydrogenation reduction, and meanwhile, the impurities are difficult to separate in the existing liquid phase analysis method and difficult to remove in the subsequent steps, so that the quality hidden danger is large; 3) trace defluorination impurities can affect the purity of subsequent amino and the quality of salt formation, so that the mixture of amino monohydrochloride and dihydrochloride is caused, and the dihydrochloride of the Relugolix key intermediate with high purity cannot be prepared.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention provides a preparation method and application of a high-purity Relugolix key intermediate, and the invention develops and prepares a high-purity Rulugol key intermediate 2- ((2, 6-difluorobenzyl) (ethoxycarbonyl) amino) -4- ((dimethylamino) methyl) -5- (4-aminophenyl) thiophene-3-formate compound by preparing an environment-friendly catalyst and developing a high-efficiency catalytic hydrogenation technology.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
a preparation method of a high-purity Relugolix key intermediate comprises the following steps:
(1) forming a complex by chitosan, palladium salt and other metal salts, and preparing a palladium-based bimetallic biomass supported catalyst by hydrothermal reaction;
(2) taking a compound A with a structural formula shown as (I) and a palladium bimetallic biomass supported catalyst in a reaction kettle, adding a solvent, and replacing the system with nitrogen atmosphere;
(3) introducing hydrogen, replacing the system into a hydrogen atmosphere, stirring for 3-12 h at the temperature of 0-60 ℃, and performing post-treatment (filtering and spin-drying the solvent) after the reaction is finished to obtain a white solid compound B shown as a structural formula (II), namely the Relugolix key intermediate.
The synthetic route is as follows:
preferably, the white solid has less than 0.01% defluorinated impurities.
The purity grade of the reagent related by the invention is above Chemical Purity (CP), and palladium salt and chitosan are purchased from Bailingwei science and technology Limited.
Preferably, the palladium salt is any one of palladium chloride, palladium acetate, palladium bromide and palladium nitrate, and more preferably palladium acetate; the other metal salt is a nickel salt, a copper salt or a cobalt salt, the nickel salt is any one of nickel chloride, nickel acetate, nickel bromide and nickel hydroxide, and the nickel salt is preferably nickel acetate; the copper salt is any one of copper chloride, copper acetate, copper bromide, copper sulfate and copper fluoride; the cobalt salt is any one of cobalt chloride, cobalt acetate, cobalt bromide and cobalt hydroxide.
Preferably, the molar ratio of chitosan, other metal salt and palladium salt is 50: 1: 0.1-1: 1: 0.1, more preferably 30: 1: 0.1, and the hydrothermal reaction temperature is 50-80 ℃, and more preferably 70 ℃.
Preferably, the preparation steps of the palladium-based bimetallic biomass supported catalyst are as follows:
(a) adding nickel acetate, palladium acetate and ethanol solvent into a four-neck flask, slowly adding chitosan, heating the system to 70 ℃, and reacting for 20 hours; cooling to room temperature, filtering to remove ethanol, rinsing the filter cake with ethanol for 3 times, and drying the solid in a vacuum drying oven at 60 ℃ for 12 hours;
(b) uniformly transferring the dried sample into a porcelain boat, and then putting the porcelain boat into a tube furnace; vacuumizing the tube furnace, and flushing the tube furnace with nitrogen for half an hour; keeping the circulation of nitrogen in the tube furnace, heating the tube furnace to 450-750 ℃ at a temperature gradient of 2 ℃/min, and keeping the tube furnace in a nitrogen atmosphere for 2 hours; then, cooling the tube furnace to room temperature; obtaining the palladium bimetallic biomass supported catalyst at different temperatures.
The prepared catalyst was stored at room temperature in a screw-capped vial without any special air protection and was named Ni-Pd @ CS- (450,550,650,750).
Preferably, the solvent in step (2) is any one or any combination of two or more of methanol, ethanol, isopropanol, tert-butanol, dichloromethane, dioxane, acetic acid, benzene and toluene; r is any one of ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl.
Preferably, the weight ratio of the palladium-based bimetallic biomass supported catalyst to the compound A is 0.001-0.01: 1.
application of the high-purity Relugolix key intermediate in preparation of 2- ((2, 6-difluorobenzyl) (ethoxycarbonyl) amino) -4- ((dimethylamino) methyl) -5- (4-aminophenyl) thiophene-3-formate dihydrochloride.
Preferably, the compound B is added into an organic solvent, stirred and dissolved, hydrogen chloride gas or hydrogen chloride solution is added at the temperature of 0-40 ℃, after the addition is finished, the temperature is kept at 0-40 ℃, stirring is carried out for 1-3 hours, filtering and washing are carried out, and reduced pressure drying is carried out at 50 ℃ to obtain the off-white solid.
Preferably, the organic solvent is one or any combination of two or more of ethyl acetate, ethanol, isopropanol, acetonitrile, dichloromethane, dioxane, ethyl acetate, benzene and toluene; the hydrogen chloride solution is any one or any combination of more than two of hydrogen chloride methanol, hydrogen chloride ethyl acetate and hydrogen chloride dioxane solution.
Compared with the prior art, the invention has the beneficial effects that:
1. the catalyst has the advantages of high activity, good stability, high dispersion degree of active components, long service life, repeated use, short flow, simple operation, easy control of reaction, simple equipment requirement and the like;
2. the prepared Relugolix key intermediate 2- ((2, 6-difluorobenzyl) (ethoxycarbonyl) amino) -4- ((dimethylamino) methyl) -5- (4-aminophenyl) thiophene-3-formate compound has high purity and good stability.
Drawings
FIG. 1 is a synthetic route diagram of the present invention.
Detailed Description
The invention is further illustrated with reference to specific examples, without however being limited thereto. Those skilled in the art can and should understand that any simple changes or substitutions based on the spirit of the present invention should fall within the protection scope of the present invention.
Example 1
The synthetic route of the invention is shown in figure 1, chitosan, palladium salt and nickel salt form a complex, and the palladium bimetallic biomass supported catalyst is prepared by hydrothermal reaction; dissolving the raw material A by using a solvent, adding a catalyst, wherein the weight ratio of the catalyst to the raw material is 0.1-1%, introducing hydrogen, heating to the temperature of 0-60 ℃, stirring for 3-12 h, carrying out a central control reaction, filtering after the reaction is finished, and spin-drying the solvent to obtain a white solid.
Preparation of palladium-series bimetallic biomass supported catalyst
Adding a nickel acetate solvent, a palladium acetate solvent and an ethanol solvent into a four-neck flask, and slowly adding chitosan, wherein the molar ratio of the chitosan to the nickel acetate to the palladium acetate is 30: 1: 0.1, the temperature of the system is raised to 70 ℃ and the reaction is carried out for 20 hours. Cooling to room temperature, filtering to remove ethanol, rinsing the filter cake with ethanol for 3 times, drying the solid in a vacuum drying oven at 60 ℃ for 12 hours, uniformly transferring the dried sample into a porcelain boat, and then putting into a tube furnace. The tube furnace was evacuated and then flushed with nitrogen for half an hour. The circulation of nitrogen gas in the tube furnace was maintained, and the tube furnace was heated to 450 ℃ (550 ℃,650 ℃,750 ℃) at a temperature gradient of 2 ℃/min and maintained for 2 hours in a nitrogen atmosphere. After that, the tube furnace was cooled to room temperature. The prepared catalyst was stored at room temperature in a screw-capped vial without any special air protection and was named Ni-Pd @ CS-450(Ni-Pd @ CS-550, Ni-Pd @ CS-650, Ni-Pd @ CS-750).
Preparation of Relugolix key intermediate
Weighing 100 g of compound A (R ═ isopropyl) and 100 g of catalyst Ni-Pd @ CS-5500.5 g, adding the mixture into a 2L hydrogenation kettle, adding 500mL of methanol, replacing the system with nitrogen atmosphere, then replacing the system with hydrogen atmosphere, stirring at room temperature for reaction for 3 hours, filtering the catalyst, leaching with methanol, concentrating the filtrate under reduced pressure to dryness, and drying under reduced pressure to obtain 92.23 g of product compound B (R ═ isopropyl), wherein the yield is 98.5%, the chemical purity is 99.6%, and the defluorination impurity is 0.008%.1H NMR(500MHz,DMSOd6)δ8.43(d,J＝8.0Hz,1H),8.29(s,1H),8.27(d,J＝5.3Hz,1H),7.78(s,1H),7.51(d,J＝6.5Hz,2H),7.27–7.23(m,1H),7.19–7.14(m,2H),6.76(s,1H),4.58(s,2H),3.88(s,3H),3.74(s,3H),2.89(t,J＝6.7Hz,2H),2.63(s,3H),2.36(t,J＝6.7Hz,2H),2.17(s,6H).
Example 2
100 g of the compound B (R ═ isopropyl) in example 1 was added with 0.5L of ethyl acetate and stirred to dissolve, 0.5L of 4M hydrogen chloride dioxane solution was added dropwise with stirring at a controlled temperature of 20 ℃, a large amount of crystals precipitated with half of the dropwise addition, the dropwise addition was completed, the mixture was stirred at 20 ℃ for 3 hours, filtered, washed with a small amount of dioxane, rinsed with ethyl acetate, washed with n-heptane, and dried at 50 ℃ under reduced pressure to obtain a white-like solid (compound D), which was easily hygroscopic, weighed in quick bags as 103g, the yield was 91%, the HPLC purity was 99.7%, and the defluorination impurity was 0.007%.
Example 3
Adding 100 g of the hydrogenated product in example 1 into 0.5L of acetonitrile, stirring for dissolving, dropwise adding 0.5L of 4M ethyl hydrogen chloride solution under stirring at the temperature of 20 ℃, separating out a large amount of crystals after half of the addition, keeping the temperature for 3 hours while stirring, filtering, washing with a small amount of acetonitrile, leaching with ethyl acetate, washing with n-heptane, drying at 50 ℃ under reduced pressure to obtain a white-like solid which is easy to absorb moisture, quickly bagging and weighing 104g, the yield is 92%, and the HPLC purity is 99.6%, wherein the defluorination impurity is 0.005%.
Example 4
Under the catalysis conditions of example 1, the catalyst can be recycled for 5 times, and the catalysis effect is not obviously reduced, which is specifically shown in table 1:
TABLE 1
Example 5
Adding 100 g of the hydrogenated product in example 1 into 0.5L of acetonitrile, stirring for dissolving, dropwise adding 0.5L of 4M hydrogen chloride dioxane solution under stirring at the temperature of 20 ℃, separating out a large amount of crystals after half of the solution is dropwise added, keeping the temperature at 20 ℃, stirring for 3 hours, filtering, washing with a small amount of acetonitrile, leaching with dioxane, washing with n-heptane, drying at 50 ℃ under reduced pressure to obtain a white-like solid, absorbing moisture easily, quickly bagging and weighing 105g, wherein the yield is 93%, the HPLC purity is 99.6%, and the defluorination impurity is 0.004%.
Example 6
Adding 100 g of the hydrogenated product in example 1 into 0.5L of dioxane, stirring for dissolving, dropwise adding 0.5L of 4M hydrogen chloride dioxane solution under stirring at the temperature of 20 ℃, separating out a large amount of crystals after half of the hydrogen chloride dioxane solution is added, keeping the temperature at 20 ℃, stirring for 3 hours, filtering, washing with a small amount of acetonitrile, leaching with dioxane, washing with n-heptane, drying at 50 ℃ under reduced pressure to obtain a white-like solid which is easy to absorb moisture, quickly bagging and weighing 108g, wherein the yield is 95%, the HPLC purity is 99.7%, and the defluorination impurity is 0.005%.
Example 7
Adding 100 g of the compound B (hydrogenated product) in example 1 into 0.5L of ethyl acetate, stirring for dissolving, dropwise adding 0.5L of 4M ethyl hydrogen chloride solution at the temperature of 20 ℃ under stirring, separating out a large amount of crystals after half of the dropwise addition, keeping the temperature at 20 ℃, stirring for 3h, filtering, washing with a small amount of ethyl acetate, rinsing with ethyl acetate, washing with n-heptane, and drying at 50 ℃ under reduced pressure to obtain a white-like solid (compound D), which is easy to absorb moisture, quickly bagged and weighed to be 105g, has the yield of 93 percent and the HPLC purity of 99.8 percent, wherein the defluorinated impurity is 0.003 percent
The Relugolix key intermediate 2- ((2, 6-difluorobenzyl) (ethoxycarbonyl) amino) -4- ((dimethylamino) methyl) -5- (4-aminophenyl) thiophene-3-formate compound prepared by the invention has high purity and small defluorination impurities, and is easy to prepare hydrochloride with corresponding high purity.
The preferred embodiments of the present invention have been described above in detail, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, many simple modifications can be made to the technical solution of the invention, including combinations of various technical features in any other suitable way, and these simple modifications and combinations should also be regarded as the disclosure of the invention, and all fall within the scope of the invention.
Claims (10)
1. A preparation method of a high-purity Relugolix key intermediate is characterized by comprising the following steps:
(1) forming a complex by chitosan, palladium salt and other metal salts, and preparing a palladium-based bimetallic biomass supported catalyst by hydrothermal reaction;
(2) taking a compound A with a structural formula shown as (I) and a palladium bimetallic biomass supported catalyst in a reaction kettle, adding a solvent, and replacing the system with nitrogen atmosphere;
(3) and replacing the system into a hydrogen atmosphere, stirring for 3-12 h at the temperature of 0-60 ℃, and performing post-treatment after the reaction is finished to obtain a white solid compound B shown as a structural formula (II), namely the Relugolix key intermediate.
2. The method for preparing the high-purity Relugolix key intermediate according to claim 1, which is characterized in that: the defluorinated impurity in the white solid is less than 0.01 percent.
3. The method for preparing the high-purity Relugolix key intermediate according to claim 1, which is characterized in that: the palladium salt is any one of palladium chloride, palladium acetate, palladium bromide and palladium nitrate; the other metal salt is nickel salt, copper salt or cobalt salt, and the nickel salt is any one of nickel chloride, nickel acetate, nickel bromide and nickel hydroxide; the copper salt is any one of copper chloride, copper acetate, copper bromide, copper sulfate and copper fluoride; the cobalt salt is any one of cobalt chloride, cobalt acetate, cobalt bromide and cobalt hydroxide.
4. The method for preparing the high-purity Relugolix key intermediate according to claim 3, wherein the method comprises the following steps: the molar ratio of chitosan to other metal salts to palladium salt is 50: 1: 0.1-1: 1: 0.1, and the hydrothermal reaction temperature is 50-80 ℃.
5. The preparation method of the high-purity Relugolix key intermediate according to claim 3, wherein the preparation steps of the palladium-based bimetallic biomass supported catalyst are as follows:
(a) adding nickel acetate, palladium acetate and ethanol solvent into a four-neck flask, slowly adding chitosan, heating the system to 70 ℃, and reacting for 20 hours; cooling to room temperature, filtering to remove ethanol, rinsing the filter cake with ethanol for 3 times, and drying the solid in a vacuum drying oven at 60 ℃ for 12 hours;
(b) uniformly transferring the dried sample into a porcelain boat, and then putting the porcelain boat into a tube furnace; vacuumizing the tube furnace, and flushing the tube furnace with nitrogen for half an hour; keeping the circulation of nitrogen in the tube furnace, heating the tube furnace to 450-750 ℃ at a temperature gradient of 2 ℃/min, and keeping the tube furnace in a nitrogen atmosphere for 2 hours; then, cooling the tube furnace to room temperature; obtaining the palladium bimetallic biomass supported catalyst at different temperatures.
6. The method for preparing the high-purity Relugolix key intermediate according to claim 1, which is characterized in that: the solvent in the step (2) is any one or any combination of more than two of methanol, ethanol, isopropanol, tert-butanol, dichloromethane, dioxane, ethyl acetate, benzene and toluene; r is any one of ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl.
7. The method for preparing the high-purity Relugolix key intermediate according to claim 1, which is characterized in that: the weight ratio of the palladium-based bimetallic biomass supported catalyst to the compound A is 0.001-0.01: 1.
8. use of the high purity Relugolix key intermediate of claim 1 for the preparation of 2- ((2, 6-difluorobenzyl) (ethoxycarbonyl) amino) -4- ((dimethylamino) methyl) -5- (4-aminophenyl) thiophene-3-carboxylate dihydrochloride.
9. Use according to claim 8, characterized in that: and adding the compound B into an organic solvent, stirring and dissolving, controlling the temperature to be 0-40 ℃, adding hydrogen chloride gas or hydrogen chloride solution, keeping the temperature to be 0-40 ℃, stirring for 1-3 h, filtering, washing, and drying under reduced pressure at 50 ℃ to obtain the off-white solid.
10. Use according to claim 9, characterized in that: the organic solvent is any one or any combination of more than two of ethyl acetate, ethanol, isopropanol, acetonitrile, dichloromethane, dioxane, ethyl acetate, benzene and toluene; the hydrogen chloride solution is any one or any combination of more than two of hydrogen chloride methanol solution, hydrogen chloride ethyl acetate solution and hydrogen chloride dioxane solution.
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Denomination of invention: Preparation method and application of a key intermediate for high-purity Relugolix Granted publication date: 20231229 Pledgee: Hangzhou United Rural Commercial Bank Co.,Ltd. Dachuang town sub branch Pledgor: ZHEJIANG CHEMTRUE BIOMEDICAL Co.,Ltd. Registration number: Y2024980015290 |