CN117327091A - Synthesis method of Rayleigh Lu Geli - Google Patents
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- 238000001308 synthesis method Methods 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 75
- 238000000034 method Methods 0.000 claims abstract description 70
- 238000006243 chemical reaction Methods 0.000 claims abstract description 69
- 230000008569 process Effects 0.000 claims abstract description 45
- 229940125773 compound 10 Drugs 0.000 claims abstract description 15
- 229940126214 compound 3 Drugs 0.000 claims abstract description 15
- 229940125898 compound 5 Drugs 0.000 claims abstract description 15
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims abstract description 15
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229940125782 compound 2 Drugs 0.000 claims abstract description 8
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims abstract description 7
- SOWRUJSGHKNOKN-UHFFFAOYSA-N 2,6-difluorobenzaldehyde Chemical compound FC1=CC=CC(F)=C1C=O SOWRUJSGHKNOKN-UHFFFAOYSA-N 0.000 claims abstract description 6
- MENYRYNFSIBDQN-UHFFFAOYSA-N 5,5-dibromoimidazolidine-2,4-dione Chemical compound BrC1(Br)NC(=O)NC1=O MENYRYNFSIBDQN-UHFFFAOYSA-N 0.000 claims abstract description 6
- YPWBPONDYDVMLX-UHFFFAOYSA-N 6-methoxypyridazin-3-amine Chemical compound COC1=CC=C(N)N=N1 YPWBPONDYDVMLX-UHFFFAOYSA-N 0.000 claims abstract description 6
- XHFGWHUWQXTGAT-UHFFFAOYSA-N dimethylamine hydrochloride Natural products CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 claims abstract description 6
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 claims abstract description 6
- XNXVOSBNFZWHBV-UHFFFAOYSA-N hydron;o-methylhydroxylamine;chloride Chemical compound Cl.CON XNXVOSBNFZWHBV-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 6
- 230000009467 reduction Effects 0.000 claims abstract description 6
- 238000006722 reduction reaction Methods 0.000 claims abstract description 6
- 125000003277 amino group Chemical group 0.000 claims abstract description 4
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 4
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 3
- 238000006268 reductive amination reaction Methods 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 50
- 239000003960 organic solvent Substances 0.000 claims description 42
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- 239000002904 solvent Substances 0.000 claims description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 17
- 230000002829 reductive effect Effects 0.000 claims description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 8
- 230000009471 action Effects 0.000 claims description 7
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- 239000010410 layer Substances 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 5
- 239000012279 sodium borohydride Substances 0.000 claims description 5
- NJTZSWLQBQJUHK-UHFFFAOYSA-N CCCP(=O)=O Chemical compound CCCP(=O)=O NJTZSWLQBQJUHK-UHFFFAOYSA-N 0.000 claims description 4
- 239000000047 product Substances 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical group C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 239000007868 Raney catalyst Substances 0.000 claims description 3
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 3
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- 239000012044 organic layer Substances 0.000 claims description 3
- 238000005804 alkylation reaction Methods 0.000 claims description 2
- 239000011230 binding agent Substances 0.000 claims description 2
- 238000005893 bromination reaction Methods 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 230000002194 synthesizing effect Effects 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
- 239000011541 reaction mixture Substances 0.000 claims 3
- 239000000463 material Substances 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 6
- 231100000024 genotoxic Toxicity 0.000 abstract description 5
- 230000001738 genotoxic effect Effects 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 9
- -1 difluorochlorobenzyl Chemical group 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Divinylene sulfide Natural products C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 230000011987 methylation Effects 0.000 description 4
- 238000007069 methylation reaction Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 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 description 3
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 238000003908 quality control method Methods 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- 229930192474 thiophene Natural products 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 108700012941 GNRH1 Proteins 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical group 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 238000006264 debenzylation reaction Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 125000006287 difluorobenzyl group Chemical group 0.000 description 2
- 238000002386 leaching Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 238000004537 pulping Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- SVDDJQGVOFZBNX-UHFFFAOYSA-N 2-chloroethyl carbonochloridate Chemical compound ClCCOC(Cl)=O SVDDJQGVOFZBNX-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 201000009273 Endometriosis Diseases 0.000 description 1
- 238000007126 N-alkylation reaction Methods 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 206010046798 Uterine leiomyoma Diseases 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 201000010260 leiomyoma Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- JOHLTMWXHJLNDE-UHFFFAOYSA-N methoxyurea Chemical compound CONC(N)=O JOHLTMWXHJLNDE-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 229950004238 relugolix Drugs 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a synthesis method of a Rayleigh Lu Geli, which comprises the following steps: reacting the compound 2 with di-tert-butyl dicarbonate to obtain a compound 3; reacting the compound 3 with dibromohydantoin to obtain a compound 4; reaction of Compound 4 with dimethylamine hydrochloride , Obtaining a compound 5; hydrolyzing the compound 5 to obtain a compound 6; condensing the compound 6 with 6-methoxy-3-aminopyridazine to obtain a compound 7; deprotection of the amino group of compound 7 affords compound 8; carrying out reductive amination on the compound 8 and 2, 6-difluorobenzaldehyde to obtain a compound 9; performing nitro reduction on the compound 9 to obtain a compound 10; compound 10 was reacted in the presence of carbonyldiimidazole and methoxyamine hydrochloride to give r. Lu Geli. Compared with the prior art, the synthesis method of the invention has the advantages of higher efficiency, avoiding potential genotoxic impurities in the prior art, mild process conditions, higher reaction yield in each step, effectively reducing the industrial production cost and safety risk, and being suitable for industrial production
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a synthesis method of a Rayleigh Lu Geli.
Background
Rayleigh Lu Geli (Relugolix), CAS number 737789-87-6, chemical name N- (4- (1- (2, 6-difluorobenzyl) -5- ((dimethylamino) methyl) -3- (6-methoxy-3-pyridazinyl) -2, 4-dioxo-1, 2,3, 4-tetrahydrothieno [2,3-d ] pyrimidin-6-yl) phenyl) -N' -methoxyurea. The medicine is a medicine commonly developed by Myovant company and the Wuta pharmaceutical industry (Takeda), is a small molecule gonadotrophin releasing hormone (GnRH) receptor antagonist, has potential to be used for uterine fibroids, endometriosis, prostatic cancer and other indications, and has a chemical structure shown in a formula I.
I is a kind of
One method of preparing rayleigh Lu Geli is disclosed in the wuta pharmaceutical industry in patent CN 100360538C. The method is shown in a synthetic route 1, wherein the yield of the pyridazine condensation step is only 26%, 10% palladium carbon is used as a catalyst in the nitro reduction step and the next to last deprotection step, hydrogen is used for pressurizing to prepare a key intermediate, and part of difluorobenzyl is removed to form unnecessary process impurities during debenzylation, so that the selection of benzyl protecting groups of amino groups is unsuitable, a methylation reagent with relatively high toxicity such as methyl iodide is needed in the final methylation step, the yield is only 17%, and the problems of difficult removal of potential metals, genotoxic impurities and the like exist.
Scheme 1
The wuta pharmaceutical industry reports a synthesis of rayleigh Lu Geli in document j.med.chem.2011,54,4998-5012, which is referred to below in scheme 2, and discloses a method for preparing rayleigh Lu Geli by nitro reduction, nucleophilic substitution, hydrolysis, acylated amine ring closure, demethoxyethyl, and nitrogen methylation. In the method, 10% palladium carbon is used, and during debenzylation, difluorobenzyl is partially removed to form unnecessary process impurities, so that the quality control of the product is difficult, the yield of the route is low, and the industrial value is low.
Scheme 2
The wuta pharmaceutical industry in patent CN104703992a discloses a process for preparing ray Lu Geli, see scheme 3 below. The method has harsh reaction conditions, needs to react under the conditions of heating and pressurizing, and has high requirements on equipment. In addition, a plurality of intermediates in the route are oily substances, have poor physical properties, need to be purified by column chromatography, have complicated operation, high cost and large industrialization difficulty.
Scheme 3
Patent CN114685468A discloses a synthesis process of nitro compound of intermediate of rayl Lu Geli, which comprises brominating thiophene methyl, condensing thiophene methyl with dimethylamine to obtain compound B, and carrying out N-alkylation reaction on the obtained compound B and difluorochlorobenzyl, wherein the alkalinity of 4-dimethylamino of thiophene is far stronger than that of amino protected by carbobenzoxy of 2-thiophene, so that the inventor of the present invention mainly obtains quaternary ammonium salt compound D when repeating the technical scheme, and the expected conversion rate of compound C is low, and therefore the practical operability and feasibility of the route are low.
In summary, the prior art has the following disadvantages:
1) The amino benzyl protecting group in the synthetic route of the patent CN100360538C is not properly selected, a highly toxic methyl iodide reagent is needed in the final synthetic step of the bulk drug, and the methylation yield is low, so that the production cost of the bulk drug is high and the quality of the bulk drug is not easy to control.
2) The amino protecting group methoxyethyl in the synthetic route of the document J.Med.chem.2011,54,4998-5012 is not properly selected, and the final synthetic step of the bulk drug needs to use a potential genotoxic substance chloroethyl chloroformate, which is not beneficial to controlling the quality of the bulk drug.
3) The intermediate design in the synthetic route of the patent CN114685468A has certain defects, the intermediate is not easy to purify, the quality control is difficult, and the industrial production cost is higher.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provide a synthesis method of the Rayleigh Lu Geli.
The research shows that the key of the synthesis of the Rui Lu Geli is the construction of a thieno-ring urea heterocycle, the prior art is mainly obtained by cyclization of pyridazine amide and orthodifluorobenzyl amine protected carbamate under a strong alkaline condition, and the technology of directly condensing and closing the ring by using the pyridazine amide and difluorobenzyl amine has not been reported yet.
Specifically, the technical scheme of the synthesis method of the Rayleigh Lu Geli provided by the invention is as follows:
a method of synthesizing a rayleigh Lu Geli comprising the steps of:
step 1: under the action of alkali, compound 2 and di-tert-butyl dicarbonate ((Boc) 2 O) to obtain a compound 3,
step 2: in an organic solvent, the compound 3 and dibromohydantoin undergo bromination reaction to obtain a compound 4,
step 3: under the condition that triethylamine is used as an acid binding agent, the compound 4 and dimethylamine hydrochloride are subjected to alkylation reaction to obtain a compound 5,
step 4: hydrolyzing the compound 5 in the presence of a base to obtain a compound 6,
step 5: under the action of propyl phosphoric anhydride (T3P), condensing the compound 6 with 6-methoxy-3-aminopyridazine to obtain a compound 7,
step 6: deprotection of the tert-butyl protected amino group in compound 7 in the presence of an acid gives compound 8,
step 7: under the action of sodium borohydride, the compound 8 and 2, 6-difluorobenzaldehyde are subjected to reductive amination to obtain a compound 9,
step 8: the compound 9 is subjected to nitro reduction to obtain a compound 10,
step 9: compound 10 was reacted in the presence of carbonyldiimidazole and methoxyamine hydrochloride to give the product of r.p. Lu Geli.
The process according to the invention, wherein in step 1 the molar ratio of compound 2 to di-tert-butyl dicarbonate is 1:2.2 to 2.8, preferably 1:2.5.
the process according to the invention, wherein in step 1 the base is triethylamine and/or 4-dimethylaminopyridine.
The process according to the invention, wherein, in step 1, the reaction temperature is 55 to 70 ℃, preferably 60 to 65 ℃.
The process according to the invention, wherein, in step 1, the reaction is carried out in an organic solvent, wherein the organic solvent is 1, 4-dioxane; the mass volume ratio (g/mL) of the compound 2 to the organic solvent is 1:5 to 1:7, preferably 1:6.
according to the method, in the step 1, after the reaction is finished, the solvent is decompressed and dried, ethanol is added into the solvent to pulp, and the mixture is filtered and dried to obtain the compound 3.
The process according to the invention, wherein in step 2, the molar ratio of compound 3 to dibromohydantoin is 1:0.5 to 0.6, preferably 1:0.55.
the process according to the invention, wherein, in step 2, the reaction temperature is 30 to 40 ℃, preferably 33 to 37 ℃.
The method according to the invention, wherein in step 2, the organic solvent is methylene chloride, wherein the mass-to-volume ratio (g/mL) of compound 3 to the organic solvent is 1:5 to 1:7, preferably 1:6.
the process according to the invention, wherein, in step 2, the reaction is carried out under light.
The method according to the present invention, wherein, after the completion of the reaction in step 2, the reaction solution is cooled to room temperature, washed with saturated sodium bicarbonate solution, the aqueous layer is extracted with dichloromethane, the dichloromethane layers are combined, the solvent is stripped off under reduced pressure, and dried to give compound 4.
The process according to the invention, wherein in step 3, the molar ratio of compound 4, triethylamine and dimethylamine hydrochloride is 1:2.5 to 3.0:1.3 to 1.6, preferably 1:2.6:1.5.
the process according to the invention, wherein, in step 3, the reaction temperature is 15 to 30 ℃, preferably 20 to 25 ℃.
The process according to the invention, wherein, in step 3, the reaction is carried out in an organic solvent, wherein the organic solvent is acetonitrile; the mass volume ratio (g/mL) of the compound 4 to the organic solvent is 1: 8-1: 12, preferably 1:10.
the method according to the present invention, wherein, after the completion of the reaction in step 3, the solvent is removed under reduced pressure, washed, dried, and dried to obtain compound 5.
The process according to the invention, wherein, in step 4, the reaction temperature is 60 to 70 ℃.
The process according to the invention, wherein in step 4 the base is sodium hydroxide and/or potassium hydroxide, wherein the molar ratio of compound 5 to base is 1: 3-1: 5, preferably 1:4.
the method according to the invention, wherein in step 4 the reaction is carried out in a solvent, wherein the solvent is a mixed solvent of ethanol and water, wherein the volume ratio of ethanol to water is 4:1; the mass volume ratio (g/mL) of the compound 5 to the solvent is 1:2.5.
in the method according to the present invention, in step 4, after the reaction, the pH is adjusted to 2 to 3 with hydrochloric acid, and a solid is precipitated, filtered, and dried to obtain Compound 6.
The process according to the invention, wherein in step 5, the molar ratio of compound 6, 6-methoxy-3-aminopyridazine, propylphosphoric anhydride is 1:1.1 to 1.3:2.2 to 2.5, preferably 1:1.2:2.4.
the process according to the invention, wherein, in step 5, the reaction temperature is 55 to 60 ℃, preferably 53 to 57 ℃.
The process according to the invention, wherein in step 5 the reaction is carried out in an organic solvent, wherein the organic solvent is DMF, wherein the mass to volume ratio (g/mL) of compound 6 to organic solvent is 1:7.
in the method according to the present invention, in step 5, after the reaction is completed, the pH is adjusted to 7.5 to 8.5, water is added, solids are precipitated, and the mixture is filtered and dried to obtain compound 7.
The process according to the invention, wherein, in step 6, the reaction temperature is 40 to 50 ℃, preferably 43 to 46 ℃.
The method according to the invention, wherein in step 6 the acid is hydrochloric acid, wherein the molar ratio of compound 7 to acid is 1:10 to 1:14, preferably 1:12.
the process according to the invention, wherein, in step 6, the reaction is carried out in an organic solvent, wherein the organic solvent is THF, wherein the mass to volume ratio (g/mL) of compound 7 to organic solvent is 1: 8-1: 12, preferably 1:10.
the method according to the present invention, wherein, in step 6, after the completion of the reaction, the pH is adjusted to 7 to 8, and the solution is desolventized under reduced pressure to dryness to obtain compound 8.
The method according to the invention, wherein, in step 7, the molar ratio of the compound 8,2,6-difluorobenzaldehyde to sodium borohydride is 1:1.1 to 1.3:1.5 to 1.8, preferably 1:1.2:1.6.
the process according to the invention, wherein, in step 7, the reaction temperature is 15 to 30 ℃, preferably 20 to 25 ℃.
The method according to the present invention, wherein, after the completion of the reaction in step 7, the reaction solution is added to a dilute aqueous hydrochloric acid solution, dichloromethane extraction is performed, and the organic layer is dried to obtain compound 9.
The process according to the invention, wherein, in step 8, the reaction temperature is 35 to 50 ℃, preferably 40 to 45 ℃.
The process according to the invention, wherein, in step 8, the reaction is carried out in an organic solvent, wherein the organic solvent is methanol; the mass volume ratio (g/mL) of the compound 9 to the organic solvent is 1: 16-1: 22, preferably 1:20.
the process according to the invention, wherein in step 8 the catalyst used for the nitroreduction is Raney nickel, wherein the mass ratio (g/g) of compound 9 to catalyst is 1:0.4.
the method according to the present invention, wherein, after the completion of the reaction in step 8, the reaction solution is filtered and the filtrate is dried to obtain compound 10.
The process according to the invention, wherein in step 9 the molar ratio of compound 10, carbonyldiimidazole and methoxyamine hydrochloride is 1:3.5 to 4.5:1.8 to 2.2, preferably 1:4.0:1.9.
the process according to the invention, wherein, in step 9, the reaction temperature is 45 to 60 ℃, preferably 50 to 55 ℃.
The process according to the invention, wherein, in step 9, the reaction is carried out in an organic solvent, wherein the organic solvent is acetonitrile; the mass volume ratio (g/mL) of the compound 10 to the organic solvent is 1: 4-1: 6, preferably 1:5.
the process according to the invention, wherein, after the end of the reaction, the solvent is stripped off under reduced pressure in step 9, gives the product of the process of the invention as Rayleigh Lu Geli.
Advantageous effects
The invention has the beneficial effects that:
(1) According to the invention, by adjusting the cyclization strategy, the pyridazine amide and the difluorobenzyl amine are directly cyclized under the action of carbonyl diimidazole to construct the target Lu Geli, and the branched methoxyurea is synchronously constructed, so that the cyclization mode is more efficient than the prior art.
(2) The invention avoids the use of potential genotoxic impurities such as methyl iodide, ethyl chloroformate and the like in the prior art, and is beneficial to the quality control of the potential genotoxic impurities in the bulk drug.
(3) The method has mild process conditions and higher reaction yield in each step, effectively reduces the industrial production cost and the safety risk, and is suitable for industrial production.
Detailed Description
The invention will be further described by means of specific embodiments in order to better understand the invention, without thereby restricting the invention to the examples described. The test methods in the examples below, for which specific conditions are not noted, were selected according to conventional methods and conditions, or according to the commercial specifications.
Unless otherwise indicated, the apparatus used in the present invention is a conventional apparatus, and the reagents used are conventional reagents.
1 HNMR is measured by a Bruker avance 400 nuclear magnetic resonance apparatus;
HRMS was measured using a Waters Xevo G2-XS QTof high resolution mass spectrometer and the ion source was an ESI source.
Example 1: preparation of Compound 3
In a four-necked flask, 10g of Compound 2 (32.6 mmol,1 eq), 17.8g of Boc were placed under nitrogen 2 O (di-tert-butyl dicarbonate) (81.55 mmol,2.5 eq), 0.2g 4-dimethylaminopyridine DMAP (0.02 w/w), 60mL 1, 4-dioxane (6V/w), heating to 60-65 ℃ and stirring for reaction for 10 hours, then decompressing and drying the solvent, adding 20mL ethanol, heating to 55-60 ℃ and pulping for 1 hour, cooling to 0-5 ℃ and preserving heat for 1 hour, filtering, leaching with ethanol, decompressing and drying at 50-55 ℃ to obtain 15.2g of compound 3, and the yield is 92%. ESI-HRMS (m/z): C 24 H 31 N 2 O 8 S[M+H+]Theoretical calculated value: 507.1796, found: 507.1792.
example 2: preparation of Compound 4
In a four-necked flask, 40g of Compound 3 (78.9 mmol,1 eq), 12.42g (43.43 mmol,0.55 eq) of dibromohydantoin, 2g (0.05 w/w) of azobisisobutyronitrile AIBN, 240mL (6 v/w) of methylene chloride, heating to 35 ℃ and keeping the temperature under illumination for 10 hours are added under the protection of nitrogen, the reaction solution is cooled to room temperature, 320mL (8 v/w) of saturated sodium bicarbonate solution is added for washing, 80mL (2 v/v) of methylene chloride is used for extracting the water layer, the methylene chloride layer is combined, the solvent is removed under reduced pressure, 120mL of ethyl acetate (3 v/v) is added, the temperature is raised to reflux and stirring is carried outDissolving, cooling to 0-5 ℃, preserving heat for 1 hour, filtering, leaching with ethanol, and drying under reduced pressure at 50-55 ℃ to obtain 43.2g of compound 4, wherein the yield is 90%. ESI-HRMS (m/z): C 24 H 30 BrN 2 O 8 S[M+H+]Theoretical calculated value: 585.0901, found: 585.0906; 1 H NMR(400MHz,CDCl 3 ):
8.40(2H,J=8Hz,d),7.86(2H,J=8Hz,d),4.82(2H,s),4.28(2H,m),1.41(18H,s),1.30(3H,m)。 13 C-NMR(100MHz,CDCl 3 ):δ161.47,149.96,147.99,146.98,138.21,138.16,133.90,130.77,128.14,124.88,83.91,61.50,27.83,14.33。
example 3: preparation of Compound 5
9.4g (115.29 mmol,1.5 eq) of dimethylamine hydrochloride, 450mL (10 v/w) of acetonitrile, 20.18g of triethylamine (199.84, 2.6 eq) were added dropwise to the flask at a temperature of 20 to 25℃and stirred for 30 minutes. 45.0g of a solution of compound 4 (76.86 mmol,1 eq) and 135ml of acetonitrile (3 v/w) are added dropwise after the temperature is reduced to 5-10 ℃, the reaction is carried out at 20-25 ℃ until the raw materials disappear, the solvent is removed by decompression, 450ml (10 v/w) of dichloromethane and 225ml (5 v/w) of water are added for washing, the solvent is removed by decompression, 90ml of isopropyl ether (2 v/w) is added, the mixture is heated to reflux, stirred and dissolved, the temperature is reduced to 0-5 ℃ for 1 hour, the mixture is filtered, and the mixture is dried at 40-45 ℃ by decompression to obtain 35.9g of compound 5, and the yield is 85%; ESI-HRMS (m/z): C 26 H 36 N 3 O 8 S[M+H+]Theoretical calculated value: 550.2218, found: 550.2215; 1 H NMR(400MHz,d6 DMSO):8.31(2H,J=8Hz,d),7.82(2H,J=8Hz,d),4.20(2H,s),3.53(2H,m),1.99(6H,s),1.39(18H,s),1.27(3H,m); 13 C-NMR(100MHz,d6 DMSO):δ162.12,149.51,147.08,138.96,136.41,135.30,130.83,123.93,83.08,60.55,54.04,44.19,27.73,27.34,13.90。
example 4: preparation of Compound 6
28g of Compound 5 (50.94 mmol,1. Eq), ethanol 56ml (2 v/w), water 14ml (0.5 v/w), potassium hydroxide 11.43g (203.77 mmol,4 eq) are placed in a four-necked flask. Heating to 60-65 ℃, keeping the temperature for reaction until the raw materials disappear, adjusting the pH to 2-3 by hydrochloric acid,solid precipitated, filtered and rinsed with 28ml of water. Adding 56ml of ethyl acetate into the filter cake for pulping, filtering, and drying at 40-45 ℃ under reduced pressure to obtain 20.3g of compound 6, wherein the yield is 95%; ESI-HRMS (m/z): C 19 H 24 N 3 O 6 S[M+H+]Theoretical calculated value: 422.1380, found: 422.1385; 1 H NMR(400MHz,d6 DMSO):11.30(1H,br),8.34(2H,J=8Hz,d),7.73(2H,J=8Hz,d),4.28(2H,s),2.56(6H,s),1.51(9H,s); 13 C-NMR(100MHz,d6 DMSO):δ167.30,152.05,150.51,147.55,139.23,131.81,131.25,126.21,123.93,124.60,114.75,82.80,79.71,53.62,42.01,28.20。
example 5: preparation of Compound 7
10g of Compound 6 (23.7 mmol,1 eq) in DMF 70ml (7 v/w) and 4.6g (28.4 mmol,1.2 eq) of 6-methoxy-3-aminopyridazine were added to a four-necked flask under nitrogen and dissolved by stirring. 15.3g of diisopropylethylamine (118.6 mmol,5 eq) is dropwise added at the temperature of 10-20 ℃, the dropwise addition is finished, the temperature is raised to 55 ℃, 36.2g (56.9 mmol,2.4 eq) of 50% ethyl acetate solution of propylphosphonic anhydride (T3P) is started to be dropwise added, the temperature is kept for reaction for 24-30 hours after the dropwise addition is finished, the pH value is regulated to 7.5-8.5 by using 4N sodium hydroxide solution, 200ml of water is slowly dropwise added, solid is separated out, and the mixture is filtered and dried to obtain 9.4g of compound 7, and the yield is 75%; ESI-HRMS (m/z): C 24 H 29 N 6 O 6 S[M+H+]Theoretical calculated value: 529.1864, found: 529.1861.
example 6: preparation of Compound 8
2g of compound 7 (3.78 mmol,1 eq), 20ml of THF (10 v/w) and 4.6g (45.3 mmol,12 eq) of refined hydrochloric acid are added into a four-necked flask, the temperature is kept at 45 ℃ for reaction for 12 hours, pH is regulated to 7-8 by liquid alkali, after the solution is decompressed to 40-50 ℃ to dryness, 200ml of dichloromethane is added for stirring and dissolving, the solution is washed twice by 100ml of x2 water, and the decompressed to 30-40 ℃ for removing the dry solvent to obtain 1.54g of compound 8 as a white solid, and the yield is 95%; ESI-HRMS (m/z): C 19 H 21 N 6 O 4 S[M+H+]Theoretical calculated value: 429.1340, found: 429.1345. 1 H-NMR(400MHz,CDCl 3 ):δ14.19(1H,s),8.37(1H,m),8.28(1H,m),7.89(2H,s),7.65(2H,d),7.23(1H,d),3.99(3H,s),3.55(2H,s),2.23(6H,s)。 13 C-NMR(100MHz,CDCl 3 ):δ165.44,164.46,161.73,153.48,146.19,140.71,131.01,130.86,123.81,123.40,119.17,118.14,108.43,54.22,54.10,43.03。
example 7: preparation of Compound 9
Nitrogen replacement, nitrogen protection, adding compound 8 (0.7 g,1.63mmol,1 eq), 2, 6-difluorobenzaldehyde (0.28 g,1.96mmol,1.2 eq), 20mL THF, heating to 45-50 ℃ and preserving heat for 1 hour, cooling to 20-25 ℃, adding sodium borohydride (0.1 g,2.64mmol,1.6 eq), dropwise adding methanol 7mL, continuing preserving heat for 3 hours, ending the reaction, dripping the reaction liquid into 20mL of dilute hydrochloric acid aqueous solution, extracting with 20mL of dichloromethane, drying the organic layer, eluting with silica gel column ethyl acetate: n-hexane 1:4 to obtain 0.76g compound 9, and obtaining a solid with a yield of 85%; ESI-HRMS (m/z): C 26 H 25 F 2 N 6 O 4 S[M+H+]Theoretical calculated value: 555.1621, found: 555.1627. 1 H-NMR(400MHz,CDCl 3 ):14.34(1H,s),9.04(1H,s),8.39(1H,s),8.24(2H,m),7.50(2H,m),7.25(1H,s),6.91(3H,m),4.51(2H,s),4.06(3H,s),3.52(2H,s),2.30(6H,s)。 13 C-NMR(100MHz,CDCl 3 ):δ166.44,165.19,162.32,160.68,146.77,140.97,132.06,131.08,130.03,123.85,120.22,118.43,113.01,111.61,108.79,54.87,54.55,43.43,38.78。
example 8: preparation of Compound 10
In a four-necked flask, compound 9 (1.0 g,1.8mmol,1 eq) was added with methanol (20 mL,20 v/w), and Raney Nickel (0.4 g,0.4 w/w) was replaced with nitrogen and hydrogen. Introducing hydrogen at 40-45 deg.C and normal pressure, reacting for 8 hr, filtering the reaction liquid, and drying the filtrate to obtain 0.8g of compound 10 with yield of 84%, ESI-HRMS (m/z): C 26 H 27 F 2 N 6 O 2 S[M+H+]Theoretical calculated value: 525.1879, found: 525.1874; 1 H NMR(400MHz,d6DMSO):14.26(1H,s),8.95(1H,s),8.33(1H,s),7.45-7.16(6H,m),6.61(2H,s),5.34(2H,s),4.51(2H,s),3.98(3H,s),3.42-3.36(2H,m),2.21(6H,s). 13 C-NMR(100MHz,d6DMSO):δ166.25,163.30,162.15,154.02,149.14,131.66,131.07,129.05,124.48,124.03,119.82,118.62,114.12,112.40,112.16,107.60,55.01,54.59,43.59,38.65。
example 9: preparation of Rayleigh Lu Geli
Under the protection of nitrogen, 0.8g of compound 10 (1.53 mmol,1 eq), 0.99g of 1, 1-carbonyldiimidazole (6.1 mmol,4.0 eq), 4mL of acetonitrile (5 v/w), heating to 45 ℃ and stirring for 4 hours, cooling to 10-15 ℃, adding 0.32g of triethylamine (3.15 mmol,2.06 eq), controlling the temperature to add 0.24g (2.9 mmol,1.9 eq) of methoxyamine hydrochloride in portions, heating to 50-55 ℃ and preserving heat for 18 hours, reacting completely, decompressing and removing acetonitrile, slowly adding 20mL of saturated ammonium chloride aqueous solution and 20mL of dichloromethane to the residue, extracting after stirring for 30 minutes, separating dichloromethane layer, decompressing and removing dichloromethane, recrystallizing the residue with ethanol to obtain 0.76g of Rai Lu Geli, yield 80%, ESI-HRMS (m/z):
C 29 H 28 F 2 N 7 O 5 S[M+H+]theoretical calculated value: 624.1835, found: 624.1827; 1 H NMR(CDCl 3 ):δ2.17(6H,s),3.62-3.82(2H,m),3.84(3H,s),4.20(3H,s),5.37(2H,s),6.94(2H,t,J=8.2Hz),7.14(1H,d,J=8.8Hz),7.22-7.67(7H,m),7.71(1H,s).
the above description of the specific embodiments of the present invention is merely a preferred embodiment of the present invention, and several optimizations of the reaction conditions in the implementation steps and improvements of the method for obtaining the intermediates related to the present invention should also be considered as protection scope of the present invention based on the synthesis route of the present invention in technical aspects, so the present invention is not limited to the above described specific embodiments. Any equivalent modifications and substitutions for the present invention will occur to those skilled in the art, and are also within the scope of the present invention.
Claims (19)
1. A method of synthesizing a rayleigh Lu Geli comprising the steps of:
step 1: under the action of alkali, compound 2 and di-tert-butyl dicarbonate ((Boc) 2 O) to obtain a compound 3,
step 2: in an organic solvent, the compound 3 and dibromohydantoin undergo bromination reaction to obtain a compound 4,
step 3: under the condition that triethylamine is used as an acid binding agent, the compound 4 and dimethylamine hydrochloride are subjected to alkylation reaction to obtain a compound 5,
step 4: hydrolyzing the compound 5 in the presence of a base to obtain a compound 6,
step 5: under the action of propyl phosphoric anhydride (T3P), condensing the compound 6 with 6-methoxy-3-aminopyridazine to obtain a compound 7,
step 6: deprotection of the tert-butyl protected amino group in compound 7 in the presence of an acid gives compound 8,
step 7: under the action of sodium borohydride, the compound 8 and 2, 6-difluorobenzaldehyde are subjected to reductive amination to obtain a compound 9,
step 8: the compound 9 is subjected to nitro reduction to obtain a compound 10,
step 9: compound 10 was reacted in the presence of carbonyldiimidazole and methoxyamine hydrochloride to give the product of r.p. Lu Geli.
2. The method according to claim 1, wherein, in step 1,
the molar ratio of compound 2 to di-tert-butyl dicarbonate is 1:2.2 to 2.8, preferably 1:2.5;
the base is triethylamine and/or 4-dimethylaminopyridine;
the reaction temperature is 55-70 ℃, preferably 60-65 ℃;
the reaction is carried out in an organic solvent, wherein the organic solvent is 1, 4-dioxane; the mass volume ratio (g/mL) of the compound 2 to the organic solvent is 1:5 to 1:7, preferably 1:6.
3. the method according to claim 2, wherein in step 1, after the reaction is completed, the solvent is removed under reduced pressure, and then ethanol is added to pulp, filter and dry to obtain the compound 3.
4. A process according to claim 1 to 3, wherein, in step 2,
the molar ratio of compound 3 to dibromohydantoin is 1:0.5 to 0.6, preferably 1:0.55;
the reaction temperature is 30-40 ℃, preferably 33-37 ℃;
the organic solvent is methylene dichloride, wherein the mass volume ratio of the compound 3 to the organic solvent is 1:5 to 1:7, preferably 1:6, preparing a base material;
the reaction was carried out under light.
5. The process according to claim 4, wherein in step 2, after the completion of the reaction, the reaction mixture is cooled to room temperature, washed with saturated sodium bicarbonate solution, the aqueous layer is extracted with dichloromethane, the dichloromethane layers are combined, the solvent is dried under reduced pressure, and compound 4 is obtained.
6. A process according to claim 1 to 3, wherein, in step 3,
the molar ratio of compound 4, triethylamine and dimethylamine hydrochloride is 1:2.5 to 3.0:1.3 to 1.6, preferably 1:2.6:1.5;
the reaction temperature is 15-30 ℃, preferably 20-25 ℃;
the reaction is carried out in an organic solvent, wherein the organic solvent is acetonitrile; the mass volume ratio (g/mL) of the compound 4 to the organic solvent is 1: 8-1: 12, preferably 1:10.
7. the process according to claim 6, wherein in step 3, after the completion of the reaction, the solvent is removed under reduced pressure, washed, dried, and dried to give compound 5.
8. A process according to claim 1 to 3, wherein, in step 4,
the reaction temperature is 60-70 ℃;
the alkali is sodium hydroxide and/or potassium hydroxide, wherein the molar ratio of the compound 5 to the alkali is 1: 3-1: 5, preferably 1:4, a step of;
the reaction is carried out in a solvent, wherein the solvent is a mixed solvent of ethanol and water, and the volume ratio of the ethanol to the water is 4:1; the mass volume ratio (g/mL) of the compound 5 to the solvent is 1:2.5.
9. the process according to claim 8, wherein in step 4, after the completion of the reaction, the pH is adjusted to 2 to 3 with hydrochloric acid, and a solid is precipitated, filtered and dried to obtain compound 6.
10. A process according to claim 1 to 3, wherein, in step 5,
the molar ratio of the compound 6, 6-methoxy-3-aminopyridazine and the propylphosphoric anhydride is 1:1.1 to 1.3:2.2 to 2.5, preferably 1:1.2:2.4;
the reaction temperature is 55-60 ℃, preferably 53-57 ℃;
the reaction is carried out in an organic solvent, wherein the organic solvent is DMF, and the mass-to-volume ratio (g/mL) of the compound 6 to the organic solvent is 1:7.
11. the method according to claim 10, wherein in step 5, after the completion of the reaction, the pH is adjusted to 7.5 to 8.5, water is added, solids are precipitated, and the mixture is filtered and dried to obtain compound 7.
12. A process according to claim 1 to 3, wherein, in step 6,
the reaction temperature is 40-50 ℃, preferably 43-46 ℃;
the acid is hydrochloric acid, wherein the molar ratio of the compound 7 to the acid is 1:10 to 1:14, preferably 1:12;
the reaction is carried out in an organic solvent, wherein the organic solvent is THF, wherein the mass to volume ratio (g/mL) of compound 7 to organic solvent is 1: 8-1: 12, preferably 1:10.
13. the process according to claim 12, wherein in step 6, after the completion of the reaction, the pH is adjusted to 7 to 8, and the reaction mixture is desolventized under reduced pressure to dryness to obtain compound 8.
14. A process according to claim 1 to 3, wherein, in step 7,
the molar ratio of the compound 8,2,6-difluorobenzaldehyde to the sodium borohydride is 1:1.1 to 1.3:1.5 to 1.8, preferably 1:1.2:1.6;
the reaction temperature is 15 to 30℃and preferably 20 to 25 ℃.
15. The process according to claim 14, wherein in step 7, after the completion of the reaction, the reaction mixture is added to a dilute aqueous hydrochloric acid solution, dichloromethane extraction is performed, and the organic layer is stripped to obtain compound 9.
16. A process according to claim 1 to 3, wherein, in step 8,
the reaction temperature is 35-50 ℃, preferably 40-45 ℃;
the reaction is carried out in an organic solvent, wherein the organic solvent is methanol; the mass volume ratio (g/mL) of the compound 9 to the organic solvent is 1: 16-1: 22, preferably 1:20, a step of;
the catalyst used for nitro reduction is Raney nickel, wherein the mass ratio of the compound 9 to the catalyst is 1:0.4.
17. the method according to claim 16, wherein in step 8, after the completion of the reaction, the reaction solution is filtered, and the filtrate is dried to obtain compound 10.
18. A process according to claim 1 to 3, wherein, in step 9,
the molar ratio of compound 10, carbonyldiimidazole and methoxyamine hydrochloride is 1:3.5 to 4.5:1.8 to 2.2, preferably 1:4.0:1.9;
the reaction temperature is 45-60 ℃, preferably 50-55 ℃;
the reaction is carried out in an organic solvent, wherein the organic solvent is acetonitrile; the mass volume ratio of the compound 10 to the organic solvent is 1: 4-1: 6, preferably 1:5.
19. the process of claim 18, wherein, after the reaction is completed in step 9, the solvent is stripped under reduced pressure to yield rayl Lu Geli.
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