CN113683499B - Method for preparing Du Weili siberian intermediate - Google Patents
Method for preparing Du Weili siberian intermediate Download PDFInfo
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- CN113683499B CN113683499B CN202111062303.2A CN202111062303A CN113683499B CN 113683499 B CN113683499 B CN 113683499B CN 202111062303 A CN202111062303 A CN 202111062303A CN 113683499 B CN113683499 B CN 113683499B
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- 238000000034 method Methods 0.000 title claims abstract description 33
- 238000006243 chemical reaction Methods 0.000 claims abstract description 59
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 35
- WFNLHDJJZSJARK-UHFFFAOYSA-N 2-chloro-6-methylaniline Chemical compound CC1=CC=CC(Cl)=C1N WFNLHDJJZSJARK-UHFFFAOYSA-N 0.000 claims abstract description 31
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 31
- 229940126214 compound 3 Drugs 0.000 claims abstract description 29
- 230000001546 nitrifying effect Effects 0.000 claims abstract description 26
- 238000000297 Sandmeyer reaction Methods 0.000 claims abstract description 22
- 239000007864 aqueous solution Substances 0.000 claims abstract description 22
- 239000002994 raw material Substances 0.000 claims abstract description 22
- 229940125782 compound 2 Drugs 0.000 claims abstract description 21
- 229940125904 compound 1 Drugs 0.000 claims abstract description 19
- 238000006467 substitution reaction Methods 0.000 claims abstract description 19
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 18
- 238000006193 diazotization reaction Methods 0.000 claims abstract description 16
- -1 2-chloro-6-methylbenzoic acid compound Chemical class 0.000 claims abstract description 14
- 238000006192 iodination reaction Methods 0.000 claims abstract description 13
- 230000026045 iodination Effects 0.000 claims abstract description 11
- 239000002904 solvent Substances 0.000 claims abstract description 10
- 239000012954 diazonium Substances 0.000 claims abstract description 8
- 150000001989 diazonium salts Chemical class 0.000 claims abstract description 8
- 239000000376 reactant Substances 0.000 claims abstract description 8
- FTGLKPMFTLNUBN-UHFFFAOYSA-N 1-chloro-2-iodo-3-methylbenzene Chemical compound CC1=CC=CC(Cl)=C1I FTGLKPMFTLNUBN-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 6
- 238000002156 mixing Methods 0.000 claims abstract description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 4
- MSYWVDNGKVMKIS-UHFFFAOYSA-N 2-chloro-6-iodobenzonitrile Chemical compound ClC1=CC=CC(I)=C1C#N MSYWVDNGKVMKIS-UHFFFAOYSA-N 0.000 claims abstract description 3
- 238000004519 manufacturing process Methods 0.000 claims abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical group [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 29
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 16
- 239000007810 chemical reaction solvent Substances 0.000 claims description 16
- 235000010288 sodium nitrite Nutrition 0.000 claims description 16
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 14
- 150000001875 compounds Chemical class 0.000 claims description 13
- 238000011282 treatment Methods 0.000 claims description 12
- 230000035484 reaction time Effects 0.000 claims description 11
- 239000007787 solid Substances 0.000 claims description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 7
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 claims description 7
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 7
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 7
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 6
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 claims description 5
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 5
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 5
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 claims description 4
- 239000012414 tert-butyl nitrite Substances 0.000 claims description 4
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 3
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 claims description 3
- 150000002826 nitrites Chemical class 0.000 claims description 3
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 3
- 235000010265 sodium sulphite Nutrition 0.000 claims description 3
- JQJPBYFTQAANLE-UHFFFAOYSA-N Butyl nitrite Chemical compound CCCCON=O JQJPBYFTQAANLE-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 claims description 2
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 claims description 2
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 claims description 2
- 235000009518 sodium iodide Nutrition 0.000 claims description 2
- 239000000725 suspension Substances 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims 1
- 238000000746 purification Methods 0.000 abstract description 7
- 230000008901 benefit Effects 0.000 abstract description 6
- 238000000926 separation method Methods 0.000 abstract description 3
- 208000012839 conversion disease Diseases 0.000 abstract description 2
- 150000004694 iodide salts Chemical class 0.000 abstract description 2
- 239000004744 fabric Substances 0.000 abstract 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- CEFMMQYDPGCYMG-UHFFFAOYSA-N 2-chloro-6-methylbenzoic acid Chemical compound CC1=CC=CC(Cl)=C1C(O)=O CEFMMQYDPGCYMG-UHFFFAOYSA-N 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 238000001816 cooling Methods 0.000 description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- SJVQHLPISAIATJ-ZDUSSCGKSA-N 8-chloro-2-phenyl-3-[(1S)-1-(7H-purin-6-ylamino)ethyl]-1-isoquinolinone Chemical compound C1([C@@H](NC=2C=3N=CNC=3N=CN=2)C)=CC2=CC=CC(Cl)=C2C(=O)N1C1=CC=CC=C1 SJVQHLPISAIATJ-ZDUSSCGKSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- 238000009776 industrial production Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 3
- 229950004949 duvelisib Drugs 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 201000003444 follicular lymphoma Diseases 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 201000004085 CLL/SLL Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- 108091007960 PI3Ks Proteins 0.000 description 2
- 102100036056 Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform Human genes 0.000 description 2
- 101710204747 Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform Proteins 0.000 description 2
- 102100036052 Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform Human genes 0.000 description 2
- 101710096503 Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 210000001744 T-lymphocyte Anatomy 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 210000003719 b-lymphocyte Anatomy 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 208000023738 chronic lymphocytic leukemia/small lymphocytic lymphoma Diseases 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000011010 flushing procedure Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000003211 malignant effect Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 229910000510 noble metal Inorganic materials 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 102000010400 1-phosphatidylinositol-3-kinase activity proteins Human genes 0.000 description 1
- XHYVBIXKORFHFM-UHFFFAOYSA-N 2-amino-6-methylbenzoic acid Chemical compound CC1=CC=CC(N)=C1C(O)=O XHYVBIXKORFHFM-UHFFFAOYSA-N 0.000 description 1
- CCYFXIJPJFSTSU-UHFFFAOYSA-N 2-chloro-6-methylbenzaldehyde Chemical compound CC1=CC=CC(Cl)=C1C=O CCYFXIJPJFSTSU-UHFFFAOYSA-N 0.000 description 1
- IKCLCGXPQILATA-UHFFFAOYSA-N 2-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Cl IKCLCGXPQILATA-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 102000038030 PI3Ks Human genes 0.000 description 1
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 229940125436 dual inhibitor Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000006713 insertion reaction Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 239000010413 mother solution Substances 0.000 description 1
- 230000000802 nitrating effect Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- ZWLPBLYKEWSWPD-UHFFFAOYSA-N o-toluic acid Chemical compound CC1=CC=CC=C1C(O)=O ZWLPBLYKEWSWPD-UHFFFAOYSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 description 1
- 229960002218 sodium chlorite Drugs 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000002341 toxic gas Substances 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/08—Preparation of carboxylic acids or their salts, halides or anhydrides from nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/14—Preparation of carboxylic acid nitriles by reaction of cyanides with halogen-containing compounds with replacement of halogen atoms by cyano groups
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention provides a method for preparing Du Weili western cloth intermediate, which comprises the following steps: (1) In a proper solvent, taking a 2-chloro-6-methylaniline compound 1 as a raw material to prepare a hydrogen chloride salt of the 2-chloro-6-methylaniline compound 1, mixing the hydrogen chloride salt with a nitrifying agent aqueous solution, and then carrying out diazotization reaction to obtain a diazonium salt of the 2-chloro-6-methylaniline; then the 3-chloro-2-iodotoluene compound 2 is prepared by the sandmeyer reaction with an iodination reagent; (2) The compound 2 reacts with reactant cyano to obtain 2-chloro-6-iodobenzonitrile compound 3 through substitution reaction; (3) The compound 3 is subjected to hydrolysis reaction to obtain a 2-chloro-6-methylbenzoic acid compound 4, and the reaction equation is as follows:
Description
Technical Field
The invention relates to the field of organic chemical synthesis, in particular to a synthesis method of Du Weili Sibuia intermediate 2-chloro-6-methylbenzoic acid.
Background
Du Weili Sibutus capsule (English name: duvelisib trade name: COPIKTA), which is a novel PI3K delta inhibitory anticancer agent developed by Verartem company. Du Weili Sibutus, also known as IPI-145 and INK-1197, is the first PI3K-delta and PI3K-gamma dual inhibitor obtained, and can effectively block PI3K-delta and PI3K-gamma kinase proteins as a small molecule inhibitor of phosphoinositide-3 kinase. These two enzymes play a key role in the growth and survival of malignant B cells and T cells: its signaling pathway causes proliferation of malignant B cells and T cells and may also play a role in the formation and maintenance of the tumor microenvironment.
Du Weili Sibutus has been marketed as FDA approved on 24 th 09 2018 for the treatment of relapsed/refractory Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL) adult patients who have received at least two prior therapies. EMA was approved by duvelisib as monotherapy for treatment of relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) after at least two prior treatments and relapsed or refractory Follicular Lymphoma (FL) after at least two prior systemic treatments, month 5 of 2021; at present, china is used for treating recurrent and refractory follicular lymphoma in clinical phase 2 test stage.
2-chloro-6-methylbenzoic acid (structure shown below) is a key intermediate for the synthesis of Duvelisib.
The synthetic routes that have been reported for 2-chloro-6-methylbenzoic acid have been disclosed mainly in the following classes:
1) Chem. Soc.,1921, vol.119,1460 and Helvetica Chimica Acta,1960, vol.43,104-113 all employ the route of cyano hydrolysis, the reaction formula is as follows:
the route has lower yield, and the intermediate cyano compound is not an easily obtained compound, has high price and is not suitable for industrial production;
2) Journal f u r praktische Chemie (Leipzig 1954), 1939, vol. <2>153,200,213, etc. reported that 2-amino-6-methylbenzoic acid was used as a starting material, and a reaction scheme for producing 2-chloro-6-methylbenzoic acid by a sandmeyer reaction between isoamyl nitrite and CuCl was as follows:
the raw materials of the route are high in price and high in cost, and the yield is only 49%;
3) J.chem.Soc.Perkin I,1995,10,1265-1272 and Synth Commun, 2005, vol.35,6,799-806, etc. adopt a route of using o-chlorobenzoic acid as raw material and using sec-butyllithium to extract hydrogen to produce carbanion to make methyl substitution under the condition of ultralow temperature-90 ℃ and the reaction formula is as follows:
the route requires a low-temperature reaction condition, inflammable sec-butyllithium is used, huge potential safety hazards exist, and the danger coefficient of industrial production operation is high;
4) Patent US20030181759A1 discloses a preparation route for performing chlorination on benzene rings by using o-methylbenzoic acid as a raw material and palladium acetate as a catalyst, wherein the reaction formula is as follows:
the need of using noble metal catalyst in this route is high in cost;
5) org.process.Res.Dev.2005, vol.9,6,1003-1008 et al report the route of 2-chloro-6-methylbenzaldehyde to 2-chloro-6-methylbenzoic acid product by oxidation with sodium chlorite, DMSO, the reaction formula is as follows:
the method has expensive and not readily available raw materials. Meanwhile, the oxidation reaction has certain potential safety hazards;
6) Bellstein J.org.chem.2016, vol.12,1503-1511 reports that 1-chloro-2-iodo-3-toluene is used as a raw material to prepare a product of 2-chloro-6-methylbenzoic acid through one-step carbo-insertion reaction under the catalysis of palladium acetate, and the reaction formula is as follows:
the route needs noble metal catalysis, and the cost is high; the raw materials are prepared from highly toxic gas carbon monoxide, the yield is only 12%, and the method is not suitable for industrialization;
in addition, routes for synthesizing 2-chloro-6-methylbenzoic acid by using cyano compounds as raw materials are reported in J.org.chem.2013, vol.78,6,2786-2791 and J.chem.Soc.1921, vol.119,1460, but expensive metal catalysts and drastic drugs are respectively used for the routes, and the routes are not suitable for industrial scale amplification;
the existing synthetic route of 2-chloro-6-methylbenzoic acid has the following main defects: 1) The use of expensive catalysts or starting materials is costly; 2) The overall yield of the reaction is low; 3) The sec-butyllithium and other dangerous-reagent are used, the reaction condition of ultralow temperature to 90 ℃ is needed, the operation difficulty is high, and the potential safety hazard is high; these factors make the above-described scheme difficult to mass-industrialize.
Therefore, development of a process route and a process of the 2-chloro-6-methylbenzoic acid, which are green, environment-friendly, high in yield, low in cost and efficient, has urgent needs and broad prospects.
Disclosure of Invention
The invention aims to provide a method for preparing Du Weili Sibutus intermediate 2-chloro-6-methylbenzoic acid, which has the advantages of easily available raw materials, simplicity and convenience in operation, environment friendliness, high product yield and high purity and is easy for industrial production.
The invention discloses a synthesis process of Du Weili Sibutus intermediate 2-chloro-6-methylbenzoic acid, which comprises the following steps:
(1) In a proper solvent, taking 2-chloro-6-methylaniline (compound 1) as a raw material to prepare hydrogen chloride salt of the 2-chloro-6-methylaniline (compound 1), mixing the hydrogen chloride salt with a nitrifying agent aqueous solution, and then carrying out diazotization reaction to obtain diazonium salt of the 2-chloro-6-methylaniline;
then carrying out Mordetiedel reaction (Sandmeyer reaction) with an iodination reagent to prepare 3-chloro-2-iodotoluene (compound 2);
(2) The compound 2 and a reactant cyano compound undergo substitution reaction to prepare 2-chloro-6-iodobenzonitrile (compound 3);
(3) The compound 3 undergoes hydrolysis reaction to obtain 2-chloro-6-methylbenzoic acid (compound 4), and the reaction equation is as follows:
step (1) of the present invention, the suitable solvent is selected from one or any combination of water, THF or acetonitrile, preferably water;
in the present invention, the nitrifying agent of the step (1) is selected from sodium nitrite NaNO 2 Nitrites (n-butyl nitrite, isoamyl nitrite or tert-butyl nitrite), preferably sodium nitrite NaNO 2 The nitrifying reagent (e.g., sodium nitrite NaNO) 2 ) The molar ratio of the compound of formula 1 to the compound of formula 1, namely 2-chloro-6-methylaniline, is 1 to 2, preferably 1.05 to 1.2, 1;
in the present invention, the mass concentration of the aqueous solution of the nitrifying agent in the step (1) is preferably 18 to 40%, more preferably 18 to 32%, most preferably 20 to 30%;
further, the temperature of the diazotization reaction in the step (1) is preferably-10 to 35 ℃, more preferably-10 to 15 ℃, and most preferably-5 to 0 ℃; the diazotisation reaction time is preferably 10 to 120 minutes, more preferably 15 to 100 minutes, and most preferably 20 to 60 minutes. In the invention, the diazotization reaction time is counted after all the raw materials are mixed, and the time of dripping the sodium nitrite aqueous solution is not included. In the present invention, the preferable dropping/slow adding of the sodium nitrite aqueous solution in the step (1) is at a temperature of-10 to 10 ℃.
In the invention, a preferable technical scheme is that 2-chloro-6-methylaniline (compound 1) is taken as a raw material to prepare hydrogen chloride salt of the 2-chloro-6-methylaniline (compound 1), and the method comprises the following steps: mixing a hydrogen chloride aqueous solution (using a concentrated hydrochloric acid and water mixture) with 2-chloro-6-methylaniline (compound 1) at a temperature of between-5 and 25 ℃ (preferably between-5 and 15 ℃), and separating out a white solid to obtain a suspension;
further, according to the preferred technical scheme, the diazonium salt of the 2-chloro-6-methylaniline is obtained by cooling a hydrogen chloride salt solution of the 2-chloro-6-methylaniline (compound 1) to a temperature of between 5 ℃ below zero and 0 ℃ and mixing the diazonium salt with an aqueous solution of a nitrifying reagent; preferably, 2-chloro-6-methylaniline is added dropwise or slowly to an aqueous solution comprising hydrogen chloride to prevent the reaction rate from being too fast;
in the present invention, the concentration of the aqueous hydrogen chloride solution in the step (1) is preferably 30 to 60% by mass, more preferably 35 to 55% by mass, and most preferably 40 to 45% by mass. In the diazotization reaction process, for example, sodium nitrite is used as a diazotizing reagent to react with hydrogen chloride salt of 2-chloro-6-methylaniline to generate diazonium salt, and the diazonium salt has the following structural formula:
after the diazotization reaction is finished, the invention does not need to carry out purification treatment on a product system, and the product system is directly involved in the subsequent reaction without treatment;
the step (1) is carried out in a reaction solvent selected from one or a combination of water, ethyl acetate and toluene;
the invention mixes diazonium salt of 2-chloro-6-methylaniline and iodination reagent and then carries out sandmeyer reaction to obtain 3-chloro-2-iodotoluene (compound 2). In the invention, the iodination reagent and a reaction solvent (such as water or ethyl acetate or toluene) are preferably mixed to obtain a mixed solution, and then the diazotization reaction obtained by the diazotization reaction is dripped into the mixed solution; because nitrogen is generated and released in the sandmeyer reaction process, the nitrogen can be well controlled to be uniformly released in a dropwise adding mode, and flushing is avoided;
in the step (1) of the invention, the iodination reagent is selected from one or any combination of copper iodide, potassium iodide or sodium iodide, preferably potassium iodide;
further, in the step (1), the molar amount of the iodination reagent is (1-2), preferably (1.1-1.3) times the molar amount of the raw material of 2-chloro-6-methylaniline (compound 1); the temperature of the sandmeyer reaction is-10 ℃ to 15 ℃, preferably 0 ℃ to 10 ℃; the sandmeyer reaction time is 20-120 minutes, preferably 20-60 minutes.
After the sandmeyer reaction is finished, the obtained product system is preferably subjected to purification treatment to obtain a 3-chloro-2-iodotoluene (compound 2) product, and the post-treatment preferably comprises the following steps:
after the step (1) of the invention is finished, the sandmeyer reaction is preferably carried out by using sodium thiosulfate, or sodium bisulphite or sodium sulfite for post-treatment;
and adding ethyl acetate and water into the product obtained by the sandmeyer reaction, washing an ethyl acetate layer by using 5-10% of sodium thiosulfate, sodium bisulphite or sodium sulfite and the like, optionally washing the ethyl acetate layer by using saturated saline, and concentrating an organic phase to directly carry out the next reaction.
In the present invention, the substitution reaction in the step (2) has the following reaction formula:
in the present invention, the substitution reaction of step (2) is performed in a reaction solvent selected from the group consisting of N, N-dimethylformamide DMF, N-dimethylacetamide DMAC, N-methylpyrrolidone NMP, DMSO, acetonitrile or toluene, preferably N, N-dimethylformamide DMF; the mass ratio (g/g) of the reaction solvent to the compound 2 is (2-20): 1, preferably (3-10): 1;
in the present invention, the reactant cyano compound in the substitution reaction in the step (2) is selected from CuCN, naCN, KCN, potassium ferricyanide, etc., preferably CuCN; the reaction temperature of the substitution reaction is selected from 75-150 ℃, preferably 90-130 ℃;
further, in the step (2), the molar ratio of the reactant cyano compound to the compound 2 in the substitution reaction is (1-2): 1, preferably (1.1-1.3): 1;
the reaction time of the substitution reaction is 8 to 24 hours, preferably 10 to 18 hours.
In the present invention, the hydrolysis reaction in the step (3) has the following reaction formula:
in the present invention, the hydrolysis reaction of the step (3) comprises the steps of:
compound 3 is taken as a raw material, and is hydrolyzed in a proper reaction solvent in the presence of a nitrifying reagent and acid to obtain compound 4.
In the present invention, the reaction solvent for the hydrolysis reaction in the step (3) is one or any combination of AcOH and water, preferably AcOH; the mass ratio of the reaction solvent to the compound 3 is (1-5): 1, preferably (1-3): 1, more preferably (1-2): 1, and even more preferably (1.2-1.5): 1;
in the present invention, in the hydrolysis reaction of the step (3), the acid is selected from sulfuric acid, hydrochloric acid, preferably concentrated sulfuric acid; the molar ratio of the acid to the compound 3 is (1-10): 1, preferably (2-7): 1;
in the present invention, the reaction temperature of the hydrolysis reaction of the step (3) is 100 to 130 ℃, preferably 110 to 125 ℃;
in the present invention, the nitrifying reagent of the step (3) is selectedFrom sodium nitrite NaNO 2 Isoamyl nitrite or tert-butyl nitrite, preferably sodium nitrite NaNO 2 The molar ratio of the nitrifying reagent to the compound 3 is (1-4): 1, preferably (1.05-3): 1, wherein the nitrifying reagent can be added in portions or in one portion; if the addition is carried out in portions, the molar ratio of nitrating agent to compound 3 is preferably from 1 to 2, preferably from 1.05 to 1.5, 1.
Compared with the prior art, the invention has the following beneficial technical effects:
the diazotization avoids sulfuric acid, phosphoric acid and the like, hydrochloric acid is used to avoid a plurality of side reactions, hydrolysis reaction, coupling reaction and tar phenomenon, and the obtained diazotized salt is directly subjected to the sandmeyer reaction (Sandmeyer reaction) to prepare 3-chloro-2-iodotoluene (compound 2) without purification treatment in water, tetrahydrofuran or acetonitrile solution, wherein the yield is more than 95%, more preferably 97.2%; in the salification reaction process, the hydrogen chloride aqueous solution can maintain the acidity after the reaction system, and forms hydrogen chloride salt with 2-chloro-6-methylaniline (compound 1), so that the salification reaction is thorough, and the generation of subsequent azo byproducts is avoided; the invention has the advantages of classical sandmeyer reaction, high reaction selectivity, less byproducts and high quality of the obtained product;
the inventors tried to react 1, 2-chloro-6-methylaniline (compound 1) directly to the cyano compound and tried CuCN with lower toxicity, but failed the reaction, which route was not viable, the results showed: the reaction products of this step are very heterogeneous, only very small amounts of products are obtained; after the second reaction is tried and the bromination or the chlorination reaction is tried on the 2-chloro-6-methylaniline (compound 1), the problem of low product yield can also occur;
the invention skillfully adopts KI iodination reaction according to the activity of 2-chloro-6-methylaniline (compound 1) through iodination reaction, and has good effect, simple separation and high yield; the iodides with higher activity and CuCN with lower toxicity are utilized for reaction, the reaction yield is high, and the purification is simple; KCN and the like are avoided;
in addition, the problems that the hydrolysis reaction in the third step is difficult and the raw materials are easy to sublimate are solved through solvent screening and optimization, particularly, a mixed solvent of acetic acid or acetic acid and water is used, and the polarity of a reaction system and the viscosity of the solvent are very suitable for the hydrolysis reaction environment of the compound 3; the inventor tries different compound solvents and proportions, the final use of the solvent containing AcOH can effectively prevent the sublimation of the product, the reaction conversion rate (the yield is about 90 percent, and 91 percent is higher) is not influenced, and the post-treatment is very simple.
The invention adopts the following route:
finally, the route adopts cheap and easily-obtained starting materials, expensive metal catalysts are not used in the whole reaction process, so that high-toxicity and inflammable reagents and gases are avoided, the reagents are easy to obtain and no catalysts are used, and particularly, the method of iodination by adopting the sandmeyer reaction is adopted, so that the utilization rate of iodine is improved; the three-step reaction has the advantages of high reaction yield, good purity, simplicity, rapidness, mild and controllable reaction conditions, obvious cost advantage, high product yield, easy separation and purification, high purity and easy industrial production.
Detailed Description
The technical scheme of the invention is described in detail through specific embodiments. However, the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention thereto.
Example 1
Preparation method of compound 2:
adding 20L of water and 13.4L of concentrated hydrochloric acid into a 100L reaction kettle (R1), cooling the reaction system to 0-15 ℃, slowly adding 4000g of 2-chloro-6-methylaniline, and precipitating white solid; cooling the reaction system to-5-0 ℃, and slowly dripping NaNO into the reaction kettle 2 The aqueous solution (2.144 kg of sodium nitrite dissolved in 7.5L of water) is dripped into the solid disappeared solution for clarification, and the reaction is carried out for 20 minutes;
8L of water, 5.6kg of potassium iodide and 16L of ethyl acetate are added into another 100L reaction kettle (R2), the temperature is reduced to 0-10 ℃, and the solution in the reaction kettle R1 is slowly dripped into the reaction kettle R2 and stirred for 30 minutes. After the completion of the reaction, 26L of ethyl acetate was added to R2, the layers were separated, 13L of ethyl acetate was added to the aqueous phase for extraction, and the organic layers were combined, washed with 40L of 5wt% sodium thiosulfate, 16L of saturated saline solution in this order, and the layers were separated, concentrated to dryness to give 7kg of compound 2 in 97.8% yield as a yellow liquid, which was directly used for the next reaction.
Example 2
Preparation method of compound 2:
adding 24mL of water and 16.8mL of concentrated hydrochloric acid into a 100mL three-necked flask (R1), cooling to-5-0 ℃, adding 5.0g of 2-chloro-6-methylaniline, precipitating white solid, and slowly dripping NaNO into R1 at-5-0 DEG C 2 The aqueous solution (2.7 g of sodium nitrite is dissolved in 10mL of water) is dripped into the solid vanishing solution to be clarified, and the mixture is stirred for 20mins for later use;
adding 10mL of water and 7.03g of KI into another 100mL three-port bottle (R2), and cooling to 0-10 ℃; slowly dripping the solution in R1 into R2, and stirring for 30 minutes to 1 hour; after the reaction was completed, 25mL of ethyl acetate was added to R2, the layers were separated, 50mL of ethyl acetate was added to the aqueous phase for extraction, the organic phases were combined, washed with 50mL of 5wt% sodium thiosulfate and 50mL of Brine in sequence, the layers were separated, the organic phases were concentrated to dryness and subjected to petroleum ether chromatography to obtain 7.96g of compound 2 in 89.6% yield as a yellow liquid, and the product was directly used for the next reaction.
Example 3
Preparation method of compound 3:
139.0g of compound 2 is added into 556mL of DMF, nitrogen is replaced twice, and the reaction temperature is 20-25 ℃; under the protection of nitrogen, 59.6g of CuCN is added, the temperature is raised to 95-100 ℃, and the reaction is carried out for 16 hours; after the raw materials are reacted completely, the temperature is reduced to 30-40 ℃, 250mL of MTBE is added, 750mL of water is added dropwise, 20g of diatomite is added after the dropwise addition is finished, solids are filtered, a filter cake is washed by 100mL of MTBE, mother liquor is layered, 250mL of MTBE is added into a water phase for extraction, and the combined organic phases are concentrated to dryness to obtain 79g of compound 3 as an off-white solid with the yield of 94.9%.
Example 4
Preparation method of compound 3 II:
adding 7.0kg of compound 2 into 28L of DMF in a 100L reaction kettle, and replacing nitrogen twice, wherein the reaction temperature is 20-25 ℃; under the protection of nitrogen, adding CuCN 2.994kg, heating to 95-100 ℃ and reacting for 16 hours; cooling to 30-40 ℃ after the raw materials react completely, adding MTBE 14L, dropwise adding 37.5L of water, adding 500g of diatomite after the dropwise adding is finished, filtering solids, flushing a filter cake by using 40L of MTBE, layering a mother solution, adding 15L of MTBE into a water phase for extraction, concentrating an organic phase to obtain a white solid, and carrying out vacuum drying at 35-40 ℃ for 16 hours to obtain 4.0kg of compound 3, wherein the yield is 95.5%;
example 5
Synthesis of Compound 4:
60g of ice was added to a 500mL three-necked flask, 150g of concentrated sulfuric acid, 60g of AcOH and 50g of Compound 3 were added with stirring, the temperature was raised to 120-125℃and stirring was carried out for 4 hours. Cooling to 30-40 ℃, and dripping NaNO 2 Aqueous solution (34.1 g sodium nitrite in 70mL water) was exothermic and had a large amount of gas evolved. Stirring overnight, and adding NaNO 2 The reaction was continued with an aqueous solution (16 g sodium nitrite in 32mL water); after the reaction was completed, 100mL of water was added, and the mixture was filtered, and the cake was washed with water and dried to obtain 50g of compound 4 in the form of white crystals with a yield of 89% and an HPLC purity of 99.04%.
Example 6
Synthesis of Compound 4:
into a 500mL three-necked flask, 80g of ice was added, 150g of concentrated sulfuric acid, 70g of AcOH,50g of Compound 3 were added under stirring, and the mixture was heated to reflux and stirred for 4 hours. Cooling to 20-30 deg.c and dropping NaNO 2 Aqueous solution (68.3 g sodium nitrite in 125mL water) was exothermic and had a large amount of gas evolved. Stirring overnight, and monitoring the reaction by HPLC; 100mL of water was added, filtered, the filter cake was rinsed with water, and dried to give 51.2g of compound 4 as white crystals in 91% yield and 99.10% HPLC purity.
It should be noted that, in each of the above steps, other auxiliary steps for collecting the product, improving the yield, improving the purity of the product, removing impurities, and the like, such as filtration, washing, extraction, purification, drying, and the like, may be adopted.
While the invention has been described with respect to the preferred embodiments, it is to be understood that the invention is not limited thereto, and that those skilled in the art will appreciate that the invention may be embodied with other forms and combinations of parts,
the foregoing examples illustrate only a few embodiments of the invention and are described in detail herein without thereby limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.
Claims (19)
1. A process for preparing a Du Weili siberian intermediate comprising the steps of:
(1) In a proper solvent, taking a 2-chloro-6-methylaniline compound 1 as a raw material to prepare a hydrogen chloride salt of the 2-chloro-6-methylaniline compound 1, mixing the hydrogen chloride salt with a nitrifying agent aqueous solution, and then carrying out diazotization reaction to obtain a diazonium salt of the 2-chloro-6-methylaniline;
then the 3-chloro-2-iodotoluene compound 2 is prepared by the sandmeyer reaction with an iodination reagent;
(2) The compound 2 reacts with reactant cyano to obtain 2-chloro-6-iodobenzonitrile compound 3 through substitution reaction;
(3) The compound 3 is subjected to hydrolysis reaction to obtain a 2-chloro-6-methylbenzoic acid compound 4, and the reaction equation is as follows:
，
the hydrolysis reaction of the step (3) comprises the following steps: taking a compound 3 as a raw material, and hydrolyzing in a proper reaction solvent in the presence of a nitrifying reagent and acid to obtain a compound 4; the nitrifying reagent is selected from sodium nitrite NaNO 2 Isoamyl nitrite or tert-butyl nitrite; the acid is selected from sulfuric acid and hydrochloric acid;
in the step (1), the molar amount of the iodination reagent is (1-2) times that of the raw material of the 2-chloro-6-methylaniline compound 1 in the sandmeyer reaction; the temperature of the sandmeyer reaction is-10-15 ℃;
said step (1), said suitable solvent being selected from one or any combination of water, THF or acetonitrile;
the nitrifying reagent in the step (1) is selected from sodium nitrite NaNO 2 Or nitrites, wherein the nitrites are selected from n-butyl nitrite, isoamyl nitrite or tert-butyl nitrite, and the molar ratio of the nitrifying reagent to the compound 2-chloro-6-methylaniline shown in the formula 1 is (1-2): 1;
the mass concentration of the nitrifying reagent aqueous solution in the step (1) is 18-40%;
the substitution reaction of the step (2) is carried out in a reaction solvent selected from N, N-dimethylformamide DMF, N-dimethylacetamide DMAC, N-methylpyrrolidone NMP, DMSO, acetonitrile or toluene; the mass gram ratio of the reaction solvent feeding amount/milliliter to the compound 2 is (2-20): 1;
in the substitution reaction of the step (2), the reactant cyano compound is one or any combination of CuCN, naCN, KCN or potassium ferricyanide;
in the substitution reaction of the step (2), the molar ratio of the reactant cyano compound to the compound 2 is (1-2): 1;
in the hydrolysis reaction of the step (3), the molar ratio of the acid to the compound 3 is (1-10): 1; the mass ratio of the reaction solvent to the compound 3 is (1-5) 1; the reaction temperature is 100-130 ℃; the molar ratio of the nitrifying reagent to the compound 3 is (1-4): 1.
2. The method according to claim 1, characterized in that: the step (1) is carried out in a reaction solvent selected from one or a combination of water, ethyl acetate and toluene;
the iodination reagent in the step (1) is selected from one or any combination of copper iodide, potassium iodide or sodium iodide.
3. The method according to claim 1 or 2, characterized in that: the reaction time of the step (1) of the sandmeyer reaction is 20-120 minutes.
4. The method according to claim 1 or 2, characterized in that: in the step (1), the molar amount of the iodination reagent is (1.1-1.3) times that of the raw material of the 2-chloro-6-methylaniline compound 1 in the sandmeyer reaction; the temperature of the sandmeyer reaction is 0-10 ℃; the reaction time of the sandmeyer reaction is 20-60 minutes.
5. The method according to claim 1 or 2, characterized in that: said step (1), said suitable solvent being selected from one or any combination of water, THF or acetonitrile;
the nitrifying reagent in the step (1) is selected from sodium nitrite NaNO 2 The molar ratio of the nitrifying reagent to the compound 2-chloro-6-methylaniline in the formula 1 is (1.05-1.2): 1;
the mass concentration of the nitrifying reagent aqueous solution in the step (1) is 18-32%.
6. The method according to claim 5, wherein: the mass concentration of the nitrifying reagent aqueous solution in the step (1) is 20-30%.
7. The method according to claim 1 or 2, characterized in that: the preparation process of the hydrogen chloride salt of the 2-chloro-6-methylaniline compound 1 in the step (1) comprises the following steps: mixing a hydrogen chloride aqueous solution and a 2-chloro-6-methylaniline compound 1 at a temperature of between 5 ℃ below zero and 25 ℃ to separate out white solid, thus obtaining suspension; the mass concentration of the hydrogen chloride aqueous solution is 30-60%.
8. The method according to claim 7, wherein: the mass concentration of the hydrogen chloride aqueous solution is 35-55%.
9. The method according to claim 8, wherein: the mass concentration of the hydrogen chloride aqueous solution is 40-45%.
10. The method according to claim 1 or 2, characterized in that: the reaction temperature of the diazotization reaction in the step (1) is-10-35 ℃; the diazotization reaction time is 10-120 minutes.
11. The method according to claim 10, wherein: the reaction temperature of the diazotization reaction in the step (1) is-10-15 ℃; the diazotization reaction time is 15-100 minutes.
12. The method according to claim 11, wherein: the reaction temperature of the diazotization reaction in the step (1) is-5-0 ℃; the diazotization reaction time is 20-60 minutes.
13. The method according to claim 1, characterized in that: the substitution reaction temperature in the step (2) is selected from 75-150 ℃; the reaction time of the substitution reaction is 8-24 hours.
14. The method according to claim 1, characterized in that: the ratio of the feeding amount/ml of the reaction solvent in the step (2) to the mass gram of the compound 2 is (3-10): 1;
in the substitution reaction in the step (2), the reaction temperature of the substitution reaction is selected from 90-130 ℃;
in the substitution reaction of the step (2), the molar ratio of the reactant cyano compound to the compound 2 is (1.1-1.3): 1;
the reaction time of the substitution reaction is 10-18 hours.
15. The method according to claim 1, characterized in that: after the sandmeyer reaction is finished, the post-treatment is performed by using sodium thiosulfate, or sodium bisulfite or sodium sulfite.
16. The method according to claim 1, characterized in that: in the hydrolysis reaction of the step (3), the nitrifying reagent can be added in batches or in one step, wherein the molar ratio of the nitrifying reagent added for the first time to the compound 3 is (1-2): 1.
17. The method according to claim 1, characterized in that: in the hydrolysis reaction of the step (3), the molar ratio of the acid to the compound 3 is (2-7) 1;
the mass ratio of the suitable reaction solvent to the compound 3 is (1-3) 1;
the reaction temperature of the hydrolysis reaction in the step (3) is 110-125 ℃;
the molar ratio of the nitrifying reagent to the compound 3 is (1.05-3): 1, wherein the nitrifying reagent can be selectively added in batches or added in one step, wherein the molar ratio of the nitrifying reagent added in batches for the first time to the compound 3 is (1.05-1.5): 1.
18. The method according to claim 17, wherein: in the hydrolysis reaction of the step (3), the mass ratio of the suitable reaction solvent to the compound 3 is (1-2): 1.
19. The method according to claim 18, wherein: the mass ratio of the suitable reaction solvent to the compound 3 is (1.2-1.5): 1.
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