CN113195454B - Preparation method of amide-like derivative and intermediate thereof - Google Patents
Preparation method of amide-like derivative and intermediate thereof Download PDFInfo
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- CN113195454B CN113195454B CN201980083057.3A CN201980083057A CN113195454B CN 113195454 B CN113195454 B CN 113195454B CN 201980083057 A CN201980083057 A CN 201980083057A CN 113195454 B CN113195454 B CN 113195454B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 150000001875 compounds Chemical class 0.000 claims abstract description 82
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 37
- 239000003960 organic solvent Substances 0.000 claims description 26
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 23
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 18
- 238000003756 stirring Methods 0.000 claims description 18
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 11
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 10
- 150000002576 ketones Chemical class 0.000 claims description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 10
- 239000007787 solid Substances 0.000 claims description 10
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 9
- 239000002841 Lewis acid Substances 0.000 claims description 9
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 239000011737 fluorine Substances 0.000 claims description 9
- 150000007517 lewis acids Chemical class 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical group [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 7
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 7
- QQZOPKMRPOGIEB-UHFFFAOYSA-N 2-Oxohexane Chemical compound CCCCC(C)=O QQZOPKMRPOGIEB-UHFFFAOYSA-N 0.000 claims description 6
- PFCHFHIRKBAQGU-UHFFFAOYSA-N 3-hexanone Chemical compound CCCC(=O)CC PFCHFHIRKBAQGU-UHFFFAOYSA-N 0.000 claims description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 6
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 150000002825 nitriles Chemical class 0.000 claims description 6
- XNLICIUVMPYHGG-UHFFFAOYSA-N pentan-2-one Chemical compound CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 claims description 6
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 claims description 6
- 238000000967 suction filtration Methods 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 235000009518 sodium iodide Nutrition 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 239000011230 binding agent Substances 0.000 claims description 4
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 claims description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 4
- 239000003444 phase transfer catalyst Substances 0.000 claims description 4
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical group [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 150000004649 carbonic acid derivatives Chemical group 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- IUSOXUFUXZORBF-UHFFFAOYSA-N n,n-dioctyloctan-1-amine;hydrochloride Chemical compound [Cl-].CCCCCCCC[NH+](CCCCCCCC)CCCCCCCC IUSOXUFUXZORBF-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 239000002516 radical scavenger Substances 0.000 claims 1
- 239000012467 final product Substances 0.000 abstract description 6
- 238000006243 chemical reaction Methods 0.000 description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical class O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 239000000543 intermediate Substances 0.000 description 13
- 239000000203 mixture Substances 0.000 description 11
- 239000012065 filter cake Substances 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- LTPVSOCPYWDIFU-UHFFFAOYSA-N 4-methoxyphenylethylamine Chemical compound COC1=CC=C(CCN)C=C1 LTPVSOCPYWDIFU-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 239000012535 impurity Substances 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 238000000746 purification Methods 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- QBEYUVIGABSXEU-UHFFFAOYSA-N 7-methoxy-3,4-dihydro-2h-isoquinolin-1-one Chemical compound C1CNC(=O)C2=CC(OC)=CC=C21 QBEYUVIGABSXEU-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- MFESCIUQSIBMSM-UHFFFAOYSA-N I-BCP Chemical compound ClCCCBr MFESCIUQSIBMSM-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 2
- 208000020016 psychiatric disease Diseases 0.000 description 2
- 201000000980 schizophrenia Diseases 0.000 description 2
- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Chemical compound O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 description 2
- VEFLKXRACNJHOV-UHFFFAOYSA-N 1,3-dibromopropane Chemical compound BrCCCBr VEFLKXRACNJHOV-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- VLQVVXRCBANNGP-UHFFFAOYSA-N 7-(3-chloropropoxy)-2-methyl-3,4-dihydroisoquinolin-1-one Chemical compound C1=C(OCCCCl)C=C2C(=O)N(C)CCC2=C1 VLQVVXRCBANNGP-UHFFFAOYSA-N 0.000 description 1
- SYBGMPNYIPZCIX-UHFFFAOYSA-N 7-hydroxy-2-methyl-3,4-dihydroisoquinolin-1-one Chemical compound C1=C(O)C=C2C(=O)N(C)CCC2=C1 SYBGMPNYIPZCIX-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- PFBUKDPBVNJDEW-UHFFFAOYSA-N dichlorocarbene Chemical class Cl[C]Cl PFBUKDPBVNJDEW-UHFFFAOYSA-N 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- -1 ethyl (4-methoxyphenylethyl) carbamate Chemical compound 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 125000004284 isoxazol-3-yl group Chemical group [H]C1=C([H])C(*)=NO1 0.000 description 1
- 125000004286 isoxazolin-3-yl group Chemical group [H]C1([H])ON=C(*)C1([H])[H] 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- YHBDIEWMOMLKOO-UHFFFAOYSA-I pentachloroniobium Chemical compound Cl[Nb](Cl)(Cl)(Cl)Cl YHBDIEWMOMLKOO-UHFFFAOYSA-I 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 235000015170 shellfish Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/24—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Provides a compound shown as a formula VI and a preparation method of an intermediate thereofThe preparation method can be used for efficiently, conveniently and safely preparing the compound shown in the formula VI, and the purity of the final product, namely the compound shown in the formula VI, is obviously improved.
Description
Technical Field
The invention relates to a preparation method of amide-like derivatives and intermediates thereof.
Background
Schizophrenia is the most serious and most harmful one of all mental diseases, and the global incidence rate is about 1-2%. The life-span morbidity of patients with schizophrenia is 0.7-0.8%, and the patients have no obvious correlation with sex, race or social boundary, and the mortality is 2-3 times higher than that of general people. Recent studies show that the social burden of mental diseases is ranked first among Chinese diseases, and exceeds the diseases of cardiovascular and cerebrovascular diseases, respiratory systems, malignant tumors and the like.
Patent WO2017084627A discloses a dopamine D-acting agent2、5-HT1AAnd 5-HT2AThe compound of the receptor and the preparation method thereof have good effect of resisting the activity of neurological diseases, and the structure of the compound is shown as follows:
However, the preparation method disclosed by the patent has the defects of high toxicity of reaction materials, overlong reaction time, high impurity content, low purity, high difficulty in industrial scale production, serious environmental pollution and the like, so that the invention provides a new synthesis thought and route, the reaction time is greatly shortened in the whole process, harsh reaction conditions are avoided, the process has strong operability, the industrial production requirement is facilitated, and the environmental protection pressure is reduced; in addition, due to the change of reaction conditions, the generation of impurities can be reduced, and the purification difficulty and cost of the final product are reduced.
Disclosure of Invention
The invention provides a method for preparing a compound shown in a formula VI and key intermediates (compounds shown in formulas III, IV and V) thereof,
wherein X1Is selected from fluorine or chlorine, and n is selected from any integer between 1 and 3.
The invention provides a preparation method of a compound shown as a formula V, which comprises the following steps: reacting a compound shown as a formula IV with a compound shown as a formula (1) in the presence of a catalyst, an alkaline substance and an organic solvent to obtain a compound shown as a formula V,
wherein n is selected from any integer between 1 and 3; the catalyst is selected from onium salt type phase transfer catalysts; the alkaline substance is selected from carbonates.
In an embodiment of the invention n is 1 or 2.
In an embodiment of the invention, the onium salt type phase transfer catalyst is selected from tetrabutylammonium bromide (TBAB), benzyltriethylammonium chloride (TEBA), trioctylammonium chloride (TCMAC) or cetyltrimethylammonium bromide (CTMAB), preferably TEBA.
In an embodiment of the invention, the carbonate is selected from sodium or potassium carbonate, preferably potassium carbonate.
In one embodiment of the invention, the organic solvent is selected from nitriles or ketones. In one embodiment of the invention, the nitrile is preferably acetonitrile and the ketone is selected from acetone, 2-butanone, pentan-2-one, pentan-3-one, hexan-2-one or hexan-3-one, preferably acetone.
In an embodiment of the present invention, in order to achieve sufficient reaction and achieve better yield, the molar ratio of the compound represented by formula iv to the compound represented by formula (2) may be 1:1 to 1:4, preferably 1:2 or 1: 3; the molar ratio of the compound shown in the formula IV to potassium carbonate is 1: 1-1: 5, preferably 1:2 or 1: 3; the molar ratio of the compound shown in the formula IV to the catalyst is selected from 50: 1-20: 1, preferably 35: 1-25: 1, and further the catalyst is selected from TEBA.
In an embodiment of the present invention, in order to completely perform the reaction, the reaction time for preparing the compound represented by the formula v from the compound represented by the formula iv and the compound represented by the formula (1) is selected from 4 to 7 hours, preferably 6 hours; the reaction temperature is 50-80 ℃, preferably 50-70 ℃.
In one embodiment of the present invention, the compound represented by the formula (1) is preferably:
when the compound represented by formula (1) of the present invention is 1-bromo-3-chloropropane, it has been surprisingly found that the content of impurities in the final product can be significantly reduced, and the purity of the final product can be significantly improved.
The invention further provides a preparation method of the compound shown in the formula VI, which comprises the following steps: reacting a compound of formula V with a compound of formula (2) in the presence of a catalyst, a carbonate and an organic solvent to obtain a compound of formula VI;
wherein X1Selected from fluorine or chlorine, preferably fluorine; n is 1 or 2, preferably 1; the compound of formula (2) may also be selected from salts with acids, such as hydrochloride.
In one embodiment of the invention, the catalyst is selected from elemental iodine, potassium iodide or sodium iodide, preferably sodium iodide; the carbonate is selected from sodium carbonate or potassium carbonate.
In one embodiment of the invention, the organic solvent is selected from nitriles or ketones. In one embodiment of the invention, the nitrile is preferably acetonitrile and the ketone is selected from acetone, 2-butanone, pentan-2-one, pentan-3-one, hexan-2-one or hexan-3-one, preferably acetone.
In an embodiment of the present invention, in order to achieve sufficient reaction and achieve better yield, the molar ratio of the compound represented by formula v to the compound represented by formula (2) may be 1:1 to 1:2, preferably 1: 1; the molar ratio of the compound shown in the formula V to potassium carbonate is selected from 1: 1-1: 5, preferably 1:2 or 1: 3; the mol ratio of the compound shown in the formula IV to the catalyst is 60: 1-30: 1, preferably 50: 1-30: 1, and further the catalyst is NaI or KI.
In one embodiment of the present invention, the compound of formula vi is preferably the following compound:
the invention further provides a preparation method of the compound shown as the formula IV, which comprises the following steps: and (3) preparing the compound shown in the formula III in the presence of Lewis acid and an organic solvent to obtain the compound shown in the formula III.
In an embodiment of the invention, the Lewis acid (Lewis acid) is selected from a molecular Lewis acid; the molecular Lewis acid is selected from boron trifluoride, ferric trichloride, aluminum trichloride, sulfur trioxide, dichlorocarbene or niobium pentachloride, and preferably the aluminum trichloride or the ferric trichloride.
In one embodiment of the invention, the organic solvent is selected from Tetrahydrofuran (THF), hexanol, methanol, toluene, N-Dimethylformamide (DMF), preferably toluene.
In one embodiment of the present invention, the molar ratio of the compound represented by formula iii to the lewis acid may be 1:1 to 1:4, preferably 1:2 or 1:3, in order to achieve sufficient reaction and achieve better yield.
In an embodiment of the present invention, in order to completely perform the reaction, the reaction time for preparing the compound of formula iv from the compound of formula iii and lewis acid may be 3 to 6 hours, preferably 4 hours; the reaction temperature is selected from 100-130 ℃, preferably 110-120 ℃.
The invention further provides a preparation method of the compound shown as the formula III, which comprises the following steps:
step 1: reacting in the presence of an acid-binding agent and an organic solvent to prepare a compound shown in a formula I;
step 2: at P2O5Reacting with methanesulfonic acid in the presence of methanesulfonic acid to prepare a compound shown as a formula II;
and step 3: reacting with methyl iodide in the presence of strong base and an organic solvent to prepare a compound shown in a formula III;
wherein the acid-binding agent is selected from pyridine or triethylamine, preferably triethylamine; the strong base is selected from NaH or KH, preferably NaH; the organic solvent in the step 1 is selected from dichloromethane; the organic solvent in the step 3 is selected from 4-Dimethylaminopyridine (DMAP) or N, N-Dimethylformamide (DMF).
In an embodiment of the invention, in step 1, for the purpose of achieving a sufficient reaction and achieving a better yield, the molar ratio of the 4-methoxyphenethylamine to the acid-binding agent may be 1: 1-1: 2, preferably 1: 1.5; the molar ratio of the 4-methoxyphenethylamine to the ethyl chloroformate is selected from 1:1 to 1:3, preferably 1:1 to 1: 1.5.
In one embodiment of the present invention, step 2 is carried out by reacting the compound of formula I with P in sufficient quantity to obtain a better yield2O5The molar ratio of (a) to (b) may be 1:1 to 2:1, preferably 1:1 to 1.5: 1.
In an embodiment of the invention, in order to achieve sufficient reaction and achieve better yield in step 3, the molar ratio of the compound represented by formula ii to the strong base may be 1:1 to 1:2, preferably 1:1 to 1: 1.5; the molar ratio of the compound represented by the formula II to methyl iodide may be 1:1 to 1:2, preferably 1:1 to 1: 1.5.
The invention further provides a method for synthesizing a compound shown in a formula VI, which is shown as follows:
wherein X1Is fluorine; n is 1 or 2, preferably 1.
The invention further discloses the application of the compound shown in the formula III, the formula IV or the formula V in preparing the compound shown in the formula VI,
wherein n is 1 or 2, preferably 1; x 1Is fluorine or chlorine, preferably fluorine.
The invention further provides the application of the compound shown in the formula V in preparing the compound shown in the formula VI, the purity of the prepared compound shown in the formula VI is more than 99 percent,
wherein n is 1 or 2, preferably 1; x1Is fluorine or chlorine, preferably fluorine.
The invention further provides a method for purifying and refining the compound shown in the formula VI, which comprises the following steps:
dissolving a crude compound shown as a formula VI in an organic solution;
adding active carbon, stirring and filtering;
thirdly, cooling and stirring at room temperature, and performing suction filtration to obtain a solid;
and fourthly, washing the solid by using an organic solvent, and drying for 5-10 hours to obtain a white powdery solid refined compound shown in the formula V.
In one embodiment of the invention, the organic solvent is selected from ketones, C1-3One or more of the alcohols of (a). In one embodiment of the invention, the ketones are selected from acetone or butanone; said C is1-3The alcohol is selected from methanol, ethanol, n-propanol or isopropanol.
In an embodiment of the present invention, the organic solvent is selected from a mixed solvent of acetone and methanol, and a volume ratio of acetone to methanol may be 5:1 to 10:1, preferably 10: 1.
In one embodiment of the invention, the step (i) further comprises a heating process, and the heating temperature can be 60-70 ℃.
In an embodiment of the invention, the stirring time in the third step may be 5 to 10 hours, preferably 5 to 7 hours.
In one embodiment of the present invention, the drying temperature in the step (iv) may be 50 to 70 ℃, preferably 50 to 60 ℃.
Advantageous effects of the invention
Compared with the preparation method disclosed in the prior art, the preparation method of the novel compound shown in the formula VI and the key intermediates (the compounds shown in the formulas III, IV and V) thereof can obviously improve the purity of the final product, and compared with the prior art, the purity reaches more than 99.8 percent and meets the standards of pharmaceutical grade raw material medicines for human; in addition, AlCl is adopted in the new preparation method3Demethylation to obtain intermediate IVThe method has the advantages of low labor protection requirement, strong operability and suitability for industrial production.
Detailed Description
The present invention will be explained in more detail with reference to examples, which are provided only for illustrating the technical solutions of the present invention and are not intended to limit the spirit and scope of the present invention.
Test conditions of the apparatus used for the experiment:
1. High Performance Liquid Chromatography (HPLC)
The instrument model is as follows: agilent 1260(DAD) binary pump liquid chromatography
And (3) chromatographic column: SHIMADZU VP-ODS C18 column (4.6X 250mm, 5 μm)
Mobile phase:
a: 0.01mol/L potassium dihydrogen phosphate, 0.1% triethylamine (pH adjusted to 2.5 with phosphoric acid) -methanol (90:10)
B: 0.01mol/L potassium dihydrogen phosphate, 0.1% triethylamine (pH adjusted to 2.5 with phosphoric acid) -methanol (20:80)
Flow rate: 1.0ml/min column temperature: 35 deg.C
Wavelength: sample volume at 210 nm: 15 μ L of
Gradient conditions (volume ratio):
example 1: preparation of ethyl (4-methoxyphenylethyl) carbamate (intermediate I)
Adding 275.0g (2.55mol) ethyl chloroformate (industrial pure, purchased from Shanghai shellfish chemical Co., Ltd.) and 2500mL of dichloromethane into a 5L reaction bottle, stirring, cooling to 0 ℃ in an ice salt bath, slowly adding 350g (2.32mol) of 4-methoxyphenethylamine (industrial pure, purchased from Shanghai Michelle chemical technology Co., Ltd.) dissolved in 1000mL of dichloromethane dropwise, and controlling the system temperature to be 0-5 ℃; after finishing the dropwise addition, slowly dropwise adding 351g (3.48mol) of triethylamine, and controlling the temperature of the system to be 5-10 ℃; after completion of the dropwise addition, the mixture was stirred at room temperature (25. + -. 5 ℃ C.) for 1 hour.
After the reaction is finished, adding 1000mL of water into the reaction solution to quench the reaction, and stirring for 5 minutes; standing and separating to obtain an organic layer, and washing the organic phase with 600mL of 1mol/L hydrochloric acid solution; the organic phase is washed with 600mL of saturated sodium chloride solution, dried over 150g of anhydrous sodium sulfate for 1 hour and filtered; the filtrate was concentrated to dryness to give a pale yellow oil, which was cooled at room temperature for 1 hour to give 508g of a pale yellow solid in 98.3% yield, MS (ESI) M/z 223.3([ M + H ] ]+)。
Example 2: preparation of 7-methoxy-3, 4-dihydroisoquinolin-1 (2H) -one (intermediate II)
Adding 510.0g (1.80mol) of phosphorus pentoxide and 2000mL of methanesulfonic acid into a 5L reaction bottle, stirring, heating in an oil bath at 125-130 ℃ until the phosphorus pentoxide is completely dissolved; and (3) stirring and cooling the mixture at room temperature until the temperature of the system is reduced to 70 ℃, and adding 1000g (2.24mol) of the intermediate I. The mixture is heated in an oil bath for 2 hours at 125 ℃.
After the reaction is finished, cooling, adding 500g of ice to quench the reaction, adding 5000mL of water into the system, extracting 6 times (1200 mL/time) with dichloromethane, combining organic phases, adding 500g of anhydrous potassium carbonate, stirring for 0.5 hour, performing suction filtration, drying the solution for 1 hour with 500g of anhydrous sodium sulfate, performing suction filtration, concentrating the filtrate to obtain a brown oily substance, cooling for 5 hours at 0 ℃, performing suction filtration, washing a filter cake with 300mL of ethyl acetate, and drying the filter cake for 8 hours at 50 +/-5 ℃ to obtain 436.5g of white-like solid with the yield of 55.1%, and MS (ESI) M/z 177.1([ M + H ] (ESI)]+)。
Example 3: preparation of 7-methoxy-3, 4-dihydroisoquinolin-1 (2H) -one (intermediate III)
Adding 54.2g (1.36mol) of 60% sodium hydride and 1000mL of N, N-dimethylformamide into a 3L reaction bottle, stirring, cooling to 0-5 ℃ in an ice salt bath, slowly dropwise adding 200g (1.13mol) of intermediate II dissolved in 500mL of N, N-dimethylformamide, and controlling the system temperature to 5-10 ℃; after the dropwise addition is finished, slowly dropwise adding 176.5g (1.24mol) of methyl iodide, and controlling the system temperature to be 10-15 ℃; after completion of the dropwise addition, the mixture was stirred at room temperature (25. + -. 5 ℃ C.) for 1 hour.
Adding 500mL of water drop into the reaction solution to quench the reaction; then 4L of water was added to mix with the reaction solution, 1630g of sodium chloride was added to saturation, extraction was performed 6 times (800 mL/time) with ethyl acetate, the organic phases were combined, washed 3 times (500 mL/time) with a saturated sodium chloride solution, and dried with 300g of anhydrous sodium sulfate for 1 hour; filtering, concentrating the filtrate to obtain 258g of brown yellow oily substance with yield over 100%, and MS (ESI) M/z 191.1([ M + H) ([ M + ]]+)。
Example 4: preparation of 7-hydroxy-2-methyl-3, 4-dihydroisoquinolin-1 (2H) -one (intermediate IV)
257.6g (1.94mol) of anhydrous aluminum chloride and 1500mL of toluene were put into a 3L reaction flask, stirred at normal temperature (25. + -. 5 ℃), and 185.0g (0.97mol) of intermediate III dissolved in 300mL of toluene was slowly added dropwise; after the dropwise addition, the mixture is heated in an oil bath to reflux (about 114 to 115 ℃), and the reaction is carried out for 4 hours under the protection of nitrogen.
After the reaction is finished, cooling the room temperature to 70 ℃, pouring out the toluene solution, pouring 2000mL of 4mol/L hydrochloric acid solution into a bottle, adding ice blocks to cool, stirring the mixture at the room temperature for 1 hour, filtering the mixture, and washing a filter cake to be neutral by using 500mL of water; dissolving the filter cake with 1000mL of 2mol/L sodium hydroxide solution, and washing with 500mL of toluene and 500mL of dichloromethane in sequence; adjusting the pH value of a water layer to 3-4 by using 36% hydrochloric acid solution, cooling in an ice bath, stirring for 0.5 hour, filtering, washing a filter cake to be neutral by using 500mL of water, drying the filter cake at 50 +/-5 ℃ for 12 hours to obtain 162.1g of white-like solid with the yield of 94.7%, and obtaining MS (ESI) M/z 177.2([ M + H ] M ]+)。
Example 5: 7- (3-Chloropropoxy) -2-methyl-3, 4-dihydroisoquinolin-1 (2H) -one (intermediate V)
156.0g (0.88mol) of intermediate IV, 277.6g (1.76mol) of the compound represented by the formula (1), 364.9g (2.64mol) of anhydrous potassium carbonate, 6.0g (0.03mol) of benzyltriethylammonium chloride and 1600mL of acetone were put into a 3L reaction flask, heated in an oil bath to reflux (about 60 to 65 ℃ C.), and stirred for 6 hours.
After the reaction is finished, filtering, and concentrating the filtrate under reduced pressure to obtain a dry solvent to obtain a yellow oily substance; dissolving in 500mL acetone, stirring at room temperature, adding 3000mL n-hexane, stirring for 1 hr under ice-bath cooling, filtering, and drying the filter cake at 50 + -5 deg.C for 6 hr to obtain off-white solid 213.2g with yield 95.8%, MS (ESI) M/z 254.1([ M + H ]]+)。
Example 6: 7- (3- (4- (6-fluorobenzo [ d ] isoxazolin-3-yl) piperidyl-1-yl) propoxy) -2-methyl-3, 4-dihydroisoquinoline-1 (2H) -one (compound shown in formula VI, crude product)
210.0g (0.83mol) of intermediate V, 223.6g (0.87mol) of the hydrochloride of the compound represented by the formula (2), 344.3g (2.64mol) of anhydrous potassium carbonate, 3.7g (0.02mol) of sodium iodide and 2100mL of acetonitrile were put into a 5L reaction flask, heated in an oil bath to reflux (about 80 to 85 ℃ C.), and stirred for 24 hours.
After the reaction, the mixture is filtered, the filtrate is placed in an ice bath to be stirred for 3 hours, the filtration is carried out, and a filter cake is dried for 3 hours at the temperature of 50 +/-5 ℃ to obtain 264.6g of yellow solid, namely a crude product of the compound shown in the formula VI, wherein the yield is 82.6%.
Example 7: 7- (3- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidyl-1-yl) propoxy) -2-methyl-3, 4-dihydroisoquinoline-1 (2H) -one (compound shown in formula VI, purified and refined)
Adding 260.0g of a crude compound shown in the formula VI, 800mL of acetone and 80mL of methanol into a 2000mL reaction bottle, heating in a water bath until the mixture flows back (about 60-65 ℃), stirring until the mixture is completely dissolved, adding 8.0g of activated carbon, stirring for 10 minutes, filtering while the mixture is hot, transferring the filtrate into the 2000mL reaction bottle, cooling at room temperature (25 +/-5 ℃), and stirring for 4 hours; suction filtration, washing with 200mL acetone, and drying the filter cake at 50 + -5 deg.C for 6 hours to obtain 180.3g of white-like powder, i.e. CY150112 product, with 79.3% yield.
1H-NMR(600MHz，CDCl3)δ2.02-2.19(m，8H)，2.60(t，2H，J＝12Hz)，2.96(t，2H，J＝12Hz),3.09-3.11(m,3H),3.18(s,3H),3.56(t,2H,J＝12Hz),4.11(t,2H,J＝6Hz),6.98-7.00(m,1H),7.06-7.10(m,2H),7.24-7.26(m,1H),7.64(d,1H,J＝6Hz)，7.74-7.76(m,1H)·MS(ESI)m/z 438.2([M+H]+)。
Example 8: comparison of the purity of the Compound of formula VI obtained by different preparation methods (end product)
Comparative sample
The synthetic route is as follows:
the preparation method comprises the following steps: reference is made to WO2017084627A, example 1 and example 5.
The purification method comprises the following steps: the purification and purification are carried out according to the method described in example 7 of the present invention.
Test sample
The synthetic route is as follows: the preparation method is carried out according to the route of examples 1-6.
The preparation method comprises the following steps: prepared as described in examples 1-6.
The purification method comprises the following steps: the product is purified and purified by the method described in reference example 7.
And (3) measuring the comparison sample and the test sample by HPLC, calculating the mass percentage of the compound shown in the formula VI in the comparison sample and the test sample according to an area normalization method, and specifically detecting results are shown in Table 1.
TABLE 1 HPLC purities of control and test samples
| Sample name | Retention time (min) | Height | Area of | HPLC content (%) |
| Comparative sample | 31.820 | 90921937 | 2717110 | 92.38 |
| Test sample | 31.219 | 98195298 | 2934467 | 99.77 |
And (3) test results: in the novel preparation process of the invention, especially when AlCl is adopted in the step 43HBr is replaced, 1-bromo-3-chloropropane is used for replacing 1, 3-dibromopropane in the step 5, the purity of the compound (final product) shown in the formula VI can be remarkably improved to over 99 percent, the quality of the raw material medicine is qualified, the raw material medicine is in accordance with the grade of the raw material medicine for human use, and meanwhile, the impurities are less, so that the subsequent impurity identification work is greatly reduced. The LC purity of the preparation process of the comparative sample is only 92.38%, the content of unknown impurities is more, and the quality of the raw material medicine is unqualified and cannot reach the level of the raw material medicine for human use.
Claims (10)
1. A preparation method of a compound shown as a formula V comprises the following steps:
1) reacting a compound shown as a formula III in the presence of Lewis acid and an organic solvent to prepare a compound shown as a formula IV, wherein the Lewis acid is aluminum trichloride;
2) reacting a compound represented by formula IV with a compound represented by formula (1) in the presence of a catalyst, a basic substance and an organic solvent to obtain a compound represented by formula V;
wherein n is selected from any integer between 1 and 3; the catalyst is selected from onium salt type phase transfer catalysts; the alkaline substance is selected from carbonates.
2. The method according to claim 1, wherein n is 1 or 2; the onium salt phase transfer catalyst is selected from tetrabutylammonium bromide, benzyltriethylammonium chloride, trioctylammonium chloride or hexadecyltrimethylammonium bromide; the carbonate is selected from sodium carbonate or potassium carbonate.
3. A method for preparing a compound shown as a formula VI comprises the following steps:
a compound of formula (V) prepared according to the process of claim 1 or 2;
reacting a compound shown in a formula V with a compound shown in a formula (2) in the presence of a catalyst, carbonate and an organic solvent;
wherein X1Selected from fluorine or chlorine; n is 1 or 2; the catalyst is selected from elementary iodine, potassium iodide or sodium iodide; the carbonate is selected from sodium carbonate or potassium carbonate.
4. The process of claim 3 wherein the compound of formula VI is:
5. the method according to claim 1, wherein the organic solvent in the step 2) is selected from ketones; the ketone is selected from acetone, 2-butanone, pentan-2-one, pentan-3-one, hexan-2-one or hexan-3-one.
6. The production process according to claim 3, wherein the organic solvent is selected from the group consisting of nitriles; the nitrile is selected from acetonitrile.
7. The preparation method according to claim 1, wherein the organic solvent in the step 1) is selected from tetrahydrofuran, hexanol, methanol, toluene or N, N-dimethylformamide.
8. The method according to claim 1, wherein the organic solvent in the step 1) is toluene.
9. The method of claim 1, wherein the compound of formula iii is prepared by:
step 1: reacting in the presence of an acid-binding agent and an organic solvent to prepare a compound shown in a formula I;
and 2, step: at P2O5Reacting with methanesulfonic acid in the presence of methanesulfonic acid to prepare a compound shown in a formula II;
and step 3: reacting with methyl iodide in the presence of strong base and an organic solvent to prepare a compound shown in a formula III;
wherein the acid scavenger is selected from pyridine or triethylamine; the strong base is selected from NaH or KH; the organic solvent in the step 1 is selected from dichloromethane; the organic solvent in the step 3 is selected from 4-dimethylaminopyridine or N, N-dimethylformamide.
10. The production process as claimed in any one of claims 3 to 4, wherein the compound represented by the formula VI is purified by a method comprising the steps of:
dissolving a crude compound shown as a formula VI in an organic solution;
secondly, adding active carbon, stirring and filtering;
thirdly, cooling and stirring at room temperature, and performing suction filtration to obtain a solid;
washing the solid with an organic solvent, and drying for 5-10 hours to obtain a refined compound shown in the formula VI;
Wherein the organic solvent is selected from ketones, C1-3One or more of the alcohols of (a); the ketones are selected from acetone or butanone; said C is1-3The alcohol is selected from methanol, ethanol, n-propanol or isopropanol.
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