CN114437007B - Preparation method of prizepride intermediate - Google Patents
Preparation method of prizepride intermediate Download PDFInfo
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- CN114437007B CN114437007B CN202011221689.2A CN202011221689A CN114437007B CN 114437007 B CN114437007 B CN 114437007B CN 202011221689 A CN202011221689 A CN 202011221689A CN 114437007 B CN114437007 B CN 114437007B
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- acetamido
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- methyl ester
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- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 50
- 238000000034 method Methods 0.000 claims abstract description 25
- LCPRNYGRYCDBOM-UHFFFAOYSA-N methyl 4-acetamido-5-chloro-2,3-dihydro-1-benzofuran-7-carboxylate Chemical compound COC(=O)C1=CC(Cl)=C(NC(C)=O)C2=C1OCC2 LCPRNYGRYCDBOM-UHFFFAOYSA-N 0.000 claims abstract description 15
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229960003863 prucalopride Drugs 0.000 claims abstract description 12
- ZPMNHBXQOOVQJL-UHFFFAOYSA-N prucalopride Chemical compound C1CN(CCCOC)CCC1NC(=O)C1=CC(Cl)=C(N)C2=C1OCC2 ZPMNHBXQOOVQJL-UHFFFAOYSA-N 0.000 claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 9
- 239000003054 catalyst Substances 0.000 claims abstract description 8
- 230000009471 action Effects 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 39
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 32
- 230000008569 process Effects 0.000 claims description 13
- 238000003756 stirring Methods 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 11
- 238000001514 detection method Methods 0.000 claims description 11
- 239000003960 organic solvent Substances 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 8
- 239000011230 binding agent Substances 0.000 claims description 8
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 8
- 239000002994 raw material Substances 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 claims description 4
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims description 4
- 238000006555 catalytic reaction Methods 0.000 claims description 3
- QGJOPFRUJISHPQ-NJFSPNSNSA-N carbon disulfide-14c Chemical compound S=[14C]=S QGJOPFRUJISHPQ-NJFSPNSNSA-N 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 10
- 239000003814 drug Substances 0.000 abstract description 10
- 238000003786 synthesis reaction Methods 0.000 abstract description 10
- 239000007858 starting material Substances 0.000 abstract description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 abstract 1
- 238000005804 alkylation reaction Methods 0.000 abstract 1
- 125000005605 benzo group Chemical group 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- -1 of formula II Chemical compound 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 239000000047 product Substances 0.000 description 14
- 239000012074 organic phase Substances 0.000 description 12
- 239000003208 petroleum Substances 0.000 description 12
- LNWKABRRGNSRPQ-UHFFFAOYSA-N methyl 4-acetamido-5-chloro-2-hydroxybenzoate Chemical compound COC(=O)C1=CC(Cl)=C(NC(C)=O)C=C1O LNWKABRRGNSRPQ-UHFFFAOYSA-N 0.000 description 10
- 239000012065 filter cake Substances 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 238000006460 hydrolysis reaction Methods 0.000 description 7
- 238000001953 recrystallisation Methods 0.000 description 7
- 238000006722 reduction reaction Methods 0.000 description 7
- 238000007363 ring formation reaction Methods 0.000 description 7
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000012046 mixed solvent Substances 0.000 description 6
- 239000008213 purified water Substances 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 5
- 238000005660 chlorination reaction Methods 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- KRMUVKSAOVLXLF-UHFFFAOYSA-N 4-amino-5-chloro-2,3-dihydro-1-benzofuran-7-carboxylic acid Chemical compound C1=C(Cl)C(N)=C2CCOC2=C1C(O)=O KRMUVKSAOVLXLF-UHFFFAOYSA-N 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- QZRSNVSQLGRAID-UHFFFAOYSA-N 4-amino-5-chloro-n-[1-(3-methoxypropyl)piperidin-4-yl]-2,3-dihydro-1-benzofuran-7-carboxamide;butanedioic acid Chemical compound OC(=O)CCC(O)=O.C1CN(CCCOC)CCC1NC(=O)C1=CC(Cl)=C(N)C2=C1OCC2 QZRSNVSQLGRAID-UHFFFAOYSA-N 0.000 description 3
- 238000005893 bromination reaction Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 229910052703 rhodium Inorganic materials 0.000 description 3
- 239000010948 rhodium Substances 0.000 description 3
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 206010010774 Constipation Diseases 0.000 description 2
- 230000031709 bromination Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005695 dehalogenation reaction Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- LCXHOHRQXZMSQN-UHFFFAOYSA-N methyl 4-acetamido-2-hydroxybenzoate Chemical compound COC(=O)C1=CC=C(NC(C)=O)C=C1O LCXHOHRQXZMSQN-UHFFFAOYSA-N 0.000 description 2
- OUEXNQRVYGYGIK-UHFFFAOYSA-N methyl 4-acetamido-5-chloro-2-methoxybenzoate Chemical compound COC(=O)C1=CC(Cl)=C(NC(C)=O)C=C1OC OUEXNQRVYGYGIK-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000003541 multi-stage reaction Methods 0.000 description 2
- 239000012285 osmium tetroxide Substances 0.000 description 2
- 229910000489 osmium tetroxide Inorganic materials 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 229950010671 prucalopride succinate Drugs 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000013341 scale-up Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- HIXAJGFVNMKLML-UHFFFAOYSA-N 1-(3-methoxypropyl)piperidin-4-amine Chemical compound COCCCN1CCC(N)CC1 HIXAJGFVNMKLML-UHFFFAOYSA-N 0.000 description 1
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 description 1
- 238000005618 Fries rearrangement reaction Methods 0.000 description 1
- 238000003309 Hoesch reaction Methods 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 238000006751 Mitsunobu reaction Methods 0.000 description 1
- 241000872931 Myoporum sandwicense Species 0.000 description 1
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 125000003172 aldehyde group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229960004909 aminosalicylic acid Drugs 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- IMNRJGSQCGFPHL-UHFFFAOYSA-N benzene;oxolane Chemical group C1CCOC1.C1=CC=CC=C1 IMNRJGSQCGFPHL-UHFFFAOYSA-N 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 231100000025 genetic toxicology Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 231100000171 higher toxicity Toxicity 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 230000008991 intestinal motility Effects 0.000 description 1
- 230000026045 iodination Effects 0.000 description 1
- 238000006192 iodination reaction Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- NCBZRJODKRCREW-UHFFFAOYSA-N m-anisidine Chemical compound COC1=CC=CC(N)=C1 NCBZRJODKRCREW-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- ALYQFGBPEGLBLW-UHFFFAOYSA-N methyl 4-amino-5-chloro-2-methoxybenzoate Chemical compound COC(=O)C1=CC(Cl)=C(N)C=C1OC ALYQFGBPEGLBLW-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- QQOXBFUTRLDXDP-UHFFFAOYSA-N p-Aminosalicylic acid methyl ester Chemical compound COC(=O)C1=CC=C(N)C=C1O QQOXBFUTRLDXDP-UHFFFAOYSA-N 0.000 description 1
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- FASDKYOPVNHBLU-ZETCQYMHSA-N pramipexole Chemical compound C1[C@@H](NCCC)CCC2=C1SC(N)=N2 FASDKYOPVNHBLU-ZETCQYMHSA-N 0.000 description 1
- 229960003089 pramipexole Drugs 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- WTVXIBRMWGUIMI-UHFFFAOYSA-N trifluoro($l^{1}-oxidanylsulfonyl)methane Chemical group [O]S(=O)(=O)C(F)(F)F WTVXIBRMWGUIMI-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans 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 hetero ring
- C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of a prucalopride intermediate 4-acetamido-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid methyl ester. The method comprises4-acetamido-5-chlorosalicylic acid methyl ester is used as a starting material, reacts with 1, 2-dibromoethane, and then directly constructs a benzo tetrahydrofuran ring through alkylation reaction on a benzene ring under the action of a catalyst to prepare the compound I, wherein the reaction equation is as follows. The preparation method can effectively shorten the reaction route, improve the operation safety, and has higher yield and purity of the target product prepared by the method.
Description
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of a prucalopride intermediate 4-acetamido-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid methyl ester.
Background
Prucapride succinate (Prucalopride Succinate), chemical name 4-amino-5-chloro-2, 3-dihydro-N- [1- (3-methoxypropyl) -4-piperidinyl]7-benzofuran carboxamide succinate, a new generation of highly selective, high affinity 5-hydroxytryptamine 4 (5-HT) developed by Belgium Movetis company 4 ) Receptor agonists, which restore impaired intestinal motility through direct effects on the intestinal wall. The European Union approves the medicine for treating chronic constipation in 10 months in 2009, the medicine is marketed in Germany in 1 month in 2010, the medicine is marketed in the United kingdom in 3 months, the medicine is approved to be marketed in 10 months in 2012 by FDA, and clinical researches show that the medicine has constant and safe curative effect on patients with severe chronic constipation, and the chemical structural formula is as follows:
the methods disclosed in the present preparation of prucalopride are numerous, most of them (such as the synthesis of the prucalopride in the literature, pharmaceutical and clinical studies, 2011, aug;19 (4): 306-307 and patents CN1164233A (CN 1071332C), CN103664912B, etc.) involve the synthesis of 4-amino-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid, i.e. of formula II, and then intermediate II and 1- (3-methoxypropyl) -4-piperidinamine undergo amidation reaction to obtain the final product prucalopride.
From the above, it can be seen that 4-amino-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid, formula II, is a key intermediate for preparing prucalopride, directly affects the production, market supply and quality problems of the pharmaceutical product. The related chemical structural formula is as follows:
at present, the synthesis of 4-amino-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid mainly comprises the following steps:
patent US5374637 (CN 1045781, EP 389037) and literature j.het.chem.,. 1980,17 (6) 1333-1335 uses m-methoxyaniline as raw material, is hydroxyethylated, cyclized, chlorinated, brominated under the action of butyllithium, and finally reacts with carbon dioxide under the action of butyllithium to obtain the product with a yield of about 18%, the route uses butyllithium and gas reactive materials (ethylene oxide, carbon dioxide) twice, requires heterogeneous reaction at-78 ℃, and its hexane solution is flammable and relatively expensive, and the isomer produced by the chlorination is separated by column chromatography, which is not suitable for industrial scale-up.
The synthesis of chem.pharm.bull, 1998,46 (1), 42-52 and pramipexole, pharmaceutical and clinical studies, 2011, (4), 306-307 and patent CN104016949a were prepared by reacting methyl 4-acetamido-2-hydroxybenzoate as starting material with 3-bromoprop-1-ene, followed by Fries rearrangement, osO 4 /NaIO 4 Oxidation reaction, naBH 4 The target product is prepared by reduction reaction, mitsunobu reaction, clasp ring, chlorination reaction and hydrolysis reaction. However, the oxidation step of the synthetic route requires the use of a highly toxic and expensive osmium tetroxide reagent, and the cyclization step uses toxic triphenylphosphine, so that the product is purified by column chromatography, and the yield is low, thus being unsuitable for industrial mass production.
The patent CN103012337A improves the process, adopts ozone to replace osmium tetroxide for oxidation, introduces sulfonate as a leaving group before cyclization reaction, but the method has longer steps, complicated operation, expensive initial compound, difficult acquisition, low overall yield and difficult industrial scale-up production, and needs to use the alkyl sulfonyl chloride with corrosiveness, irritation and genotoxicity.
The patent CN102942542A adopts the same strategy to prepare a target product, ruthenium trichloride or a hydrate/periodate composite catalyst thereof is used for oxidizing to prepare aldehyde group, and halogen, p-toluenesulfonyloxy, trifluoromethylsulfonyloxy or benzenesulfonyloxy are used as leaving groups before cyclization reaction.
In the patent CN104529960A, 4-amino-2-hydroxybenzoic acid methyl ester is used as a starting material, firstly, an amino group is protected by a trifluoroacetyl group, then, chloroacetyl group is introduced by Friedel-Crafts acylation reaction, and then, the target product is prepared by cyclization, reduction, chlorination, hydrolysis and other reactions in sequence. However, the technology adopts trifluoroacetic anhydride with higher price to introduce a protecting group, and adopts Raney Ni with higher toxicity and danger as a catalyst, so that the industrial large-scale production is difficult.
The process described above was modified by the process described in patent CN106316998A, which uses methyl 2-methoxy-4-acetamido-5-chlorobenzoate as the starting material to prepare the target product. However, the hydrazine hydrate which is a highly toxic substance is adopted for reduction, the operation risk is high, and meanwhile, the ester bond and the amide bond in the substrate structure are extremely easy to be aminated due to the high alkalinity of the hydrazine hydrate, and the amplification condition is not provided.
Chemical Process Research, vol.870, chapter 8,Washington:American Chemical Society,2003,125-139 uses methyl 4-acetamido-5-chlorosalicylate (methyl 4-acetamido-2-hydroxy-5-chlorobenzoate) as raw material, and is obtained by bromination, bromoethylation, cyclization and hydrolysis reaction, the reaction condition is mild, and the yield is 29%. This process has many problems in the final hydrolysis reaction, for example: 1. the hydrolysis reaction takes more than 15 hours, and the raw materials are not completely reacted; 2. the purity of the substrate (4-acetamido-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid methyl ester) prepared by the literature method is poor, and if 2 protecting groups are directly hydrolyzed without purification, a plurality of impurities are generated, so that the quality of a target product is difficult to ensure, and meanwhile, the difficulty of purification is increased, and the final product is influenced to reach the drug standard.
The patent CN107337658A and the synthesis of the literature prucalopride succinate, journal of Chinese medicine industry, 2012,43 (1), 5-8 take p-aminosalicylic acid as a starting material, and the target product is prepared through multi-step reaction. However, bromine is adopted for bromination reaction, so that the toxicity is high, sulfonyl chloride with stronger corrosiveness is used for chlorination reaction, and zinc powder is used in large quantity, so that the pollution is serious.
The literature praziram key intermediate 4-amino-5-chloro-2, 3-dihydro-7-benzofuran benzoic acid is researched by synthesis process, china pharmaceutical industry, 2016,25 (2), and 38-40 uses 2-methoxy-4-acetamido-5-chlorobenzoic acid methyl ester as a starting material to prepare a target product through multi-step reaction. In the process, bromine with high toxicity is used for bromination, and metal sodium is used for dehalogenation coupling, so that the steps are prolonged, and the large-scale production is difficult.
The literature Synlett,1993, (4) 269-270 takes 4-acetamido-2-hydroxybenzoic acid methyl ester as raw material, and is prepared by cyclization after chlorination, iodination and trimethylsilyl ethynylation, hydrogenation reduction under rhodium catalysis, and finally hydrolysis, and the total yield is 38%. The use of expensive silicon and rhodium reagents in the route is not suitable for mass production.
The reference J.Am.chem.Soc.,1978,100 (15) uses methyl 2-methoxy-4-amino-5-chlorobenzoate as raw material, and makes it undergo the processes of Houben-Hoesch reaction, cyclization, reduction and hydrolysis reaction so as to obtain the invented target product. The literature does not report yields, and expensive rhodium catalysts are also used for the reduction reaction.
In summary, the existing preparation method of 4-amino-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid has a plurality of problems, and most processes are used for preparing 4-acetamido-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid methyl ester through various ways and then hydrolyzing to obtain a target product, so that the 4-acetamido-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid methyl ester, namely the formula I, is also used as a key intermediate for preparing prucalopride, and directly influences the production, market supply and quality problems of the medicine.
In view of the defects existing in the prior art when 4-acetamido-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid methyl ester is prepared, a preparation process which is simple and convenient to operate, mild in reaction condition, safe in operation process, high in product yield and high in purity and is suitable for industrial production of 4-acetamido-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid methyl ester is still a problem to be solved.
Disclosure of Invention
Aiming at a plurality of problems existing in the prior preparation of the prucalopride related intermediate 4-acetamido-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid methyl ester, the invention provides a preparation method of 4-acetamido-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid methyl ester. The method has mild reaction conditions, safe and simple operation process, and the prepared target product has higher purity and yield.
The invention is realized by the following technical scheme:
the preparation method of the prucalopride intermediate 4-acetamido-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid methyl ester is characterized in that 4-acetamido-5-chlorosalicylic acid methyl ester (4-acetamido-2-hydroxy-5-chlorobenzoic acid methyl ester), namely SM-1, is used as a reaction raw material, and reacts with 1, 2-dibromoethane in an organic solvent under the action of an acid binding agent to prepare an intermediate I-1, wherein the intermediate I-1 is subjected to catalytic reaction by a catalyst to prepare a compound 4-acetamido-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid methyl ester, and the reaction formula is as follows:
a preparation method of a prucalopride intermediate 4-acetamido-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid methyl ester shown in formula I specifically comprises the following steps:
step 1, adding 4-acetamido-5-chlorosalicylic acid methyl ester, namely SM-1 and an acid binding agent, into an organic solvent A, uniformly stirring at a controlled temperature, slowly dripping 1, 2-dibromoethane, continuously reacting until TLC detection reaction is complete, and preparing an intermediate I-1 through post treatment;
step 2. AlCl is processed 3 Adding the mixture into the anhydrous organic solvent B, stirring uniformly after adding, adding the anhydrous organic solvent B solution of the intermediate I-1 by controlling the temperature, heating, continuing to react until TLC detection reaction is complete, and performing post-treatment to obtain the compound I.
Preferably, the acid binding agent in step 1 is selected from Na 2 CO 3 ，NaHCO 3 ，K 2 CO 3 ，KHCO 3 One or a combination of them, preferably Na 2 CO 3 。
Preferably, the organic solvent a in step 1 is selected from one or a combination of N, N-dimethylformamide, N-dimethylacetamide, acetonitrile, acetone, preferably N, N-dimethylformamide.
Preferably, the molar ratio of SM-1 to acid-binding agent in step 1 is 1:1.0 to 1.5, preferably 1:1.2.
Preferably, the reaction molar ratio of SM-1 to 1, 2-dibromoethane described in step 1 is 1:1.3 to 2.2, preferably 1:1.7.
Preferably, the reaction temperature described in step 1 is from 40 to 90 ℃, preferably from 50 to 55 ℃.
In a preferred embodiment, the post-treatment step in step 1 is: pouring the reaction solution into warm water, stirring, naturally cooling to room temperature, stirring for crystallization, filtering, and recrystallizing a filter cake with toluene to obtain an intermediate I-1; preferably, the temperature of the warm water is 40-55 ℃.
Preferably, the organic solvent B in step 2 is selected from one or a combination of dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride, carbon disulfide, nitromethane, nitrobenzene, preferably dichloromethane.
Preferably, I-1 and AlCl as described in step 2 3 The molar ratio of the feed is 1:0.1-1.0, preferably 1:0.3.
Preferably, the temperature controlled in the step 2 when the solution I-1 is added is-5-10 ℃; the reaction temperature is 15 to 30℃and preferably 20 to 25 ℃.
In a preferred embodiment, the post-treatment step in step 2 is: adding dilute hydrochloric acid at controlled temperature, separating to obtain organic phase, extracting aqueous phase with dichloromethane, mixing organic phases, washing with purified water, drying, filtering, concentrating the filtrate under reduced pressure to dryness, and concentrating with petroleum ether/ethyl acetate (V) Petroleum ether :V Acetic acid ethyl ester Recrystallizing the mixed solvent of =2:1) to obtain a compound I; preferably, the temperature is controlled to be-5 to 5 ℃ when dilute hydrochloric acid is added.
The invention has the beneficial effects that:
the invention provides a simple and efficient method for preparing a prucalopride intermediate 4-acetamido-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid methyl ester. The invention adopts AlCl 3 As a catalyst, the benzene ring is directly alkylated to construct the benzene tetrahydrofuran ring, and compared with the dehalogenation coupling method in the prior art and the method of adopting chloroacetyl chloride for acylation reaction and then reduction, the method can effectively shrinkShort reaction route and safer operation. The whole synthesis method is simple to operate, and the prepared target product has high yield and purity, and is suitable for industrial production.
Detailed Description
The invention is further illustrated by the following examples, with the understanding that: the examples of the present invention are intended to be illustrative of the invention and not to be limiting of the invention, so that simple modifications to the invention which are based on the method of the invention are within the scope of the invention as claimed.
In the following examples, various processes and methods, which are not described in detail, are conventional methods well known in the art.
Synthesis of I-1:
example 1
1, 2-Dibromoethane (31.94 g,0.17 mol), na 2 CO 3 (12.72 g,0.12 mol) is added into N, N-dimethylformamide (200 ml), after the temperature is controlled to be 50-55 ℃ and stirred uniformly, a solution of 4-acetamido-5-chlorosalicylic acid methyl ester (4-acetamido-2-hydroxy-5-chlorobenzoic acid methyl ester, SM-1, 24.36g,0.10 mol) and N, N-dimethylformamide (50 ml) are slowly added dropwise, the reaction is continued until TLC detection reaction is complete, the reaction solution is poured into warm water (600 ml) with the temperature of 45-50 ℃ and stirred and cooled naturally to room temperature, stirred and crystallized, filtered, and a filter cake is recrystallized by toluene to obtain an intermediate I-1 with the yield of 95.7% and the purity of 99.0%.
Example 2
1, 2-Dibromoethane (41.33 g,0.22 mol), KHCO 3 (12.01 g,0.12 mol) is added into N, N-dimethylformamide (200 ml), after the temperature is controlled to be 50-55 ℃ and stirred uniformly, 4-acetamido-5-chlorosalicylic acid methyl ester (24.35 g,0.10 mol) solution of N, N-dimethylformamide (50 ml) is slowly added dropwise, the reaction is continued until TLC detection reaction is completed, the reaction solution is poured into warm water (600 ml) with the temperature of 45-50 ℃ and stirred and naturally cooled to room temperature, stirred and crystallized, and filtered, and a filter cake is recrystallized by toluene to obtain an intermediate I-1 with the yield of 94.4% and the purity of 97.3%.
Example 3
1, 2-Dibromoethane (43.21 g,0.23 mol), K 2 CO 3 (16.58 g,0.12 mol) is addedAdding into N, N-dimethylformamide (200 ml), uniformly stirring at 50-55 ℃, slowly dripping N, N-dimethylformamide (50 ml) solution of 4-acetamido-5-chlorosalicylic acid methyl ester (24.38 g,0.10 mol), continuing to react until TLC detection reaction is complete, pouring the reaction solution into warm water (600 ml) at 45-50 ℃ for stirring and naturally cooling to room temperature, stirring for crystallization, filtering, recrystallizing a filter cake by toluene to obtain an intermediate I-1, wherein the yield is 90.1%, and the purity is 97.1%.
Example 4
1, 2-Dibromoethane (24.42 g,0.13 mol) NaHCO 3 (10.08 g,0.12 mol) is added into N, N-dimethylacetamide (200 ml), after the temperature is controlled between 60 and 65 ℃ and stirring is carried out uniformly, 4-acetamido-5-chlorosalicylic acid methyl ester (24.36 g,0.10 mol) solution of N, N-dimethylacetamide (50 ml) is slowly added dropwise, the reaction is continued until TLC detection reaction is completed, the reaction solution is poured into warm water (600 ml) with the temperature of 45 to 50 ℃ and stirred and naturally cooled to room temperature, stirring crystallization is carried out, filtration is carried out, and a filter cake is obtained after toluene recrystallization, thus obtaining an intermediate I-1 with the yield of 93.5% and the purity of 98.8%.
Example 5
1, 2-Dibromoethane (22.54 g,0.12 mol), na 2 CO 3 (12.72 g,0.12 mol) is added into N, N-dimethylformamide (200 ml), after the temperature is controlled to be 50-55 ℃ and stirred uniformly, 4-acetamido-5-chlorosalicylic acid methyl ester (24.34 g,0.10 mol) solution of N, N-dimethylformamide (50 ml) is slowly added dropwise, the reaction is continued until TLC detection reaction is completed, the reaction solution is poured into warm water (600 ml) with the temperature of 45-50 ℃ and stirred and naturally cooled to room temperature, stirred and crystallized, and filtered, and a filter cake is recrystallized by toluene to obtain an intermediate I-1 with the yield of 89.7% and the purity of 99.1%.
Example 6
1, 2-Dibromoethane (31.94 g,0.17 mol), na 2 CO 3 (15.90 g,0.15 mol) is added into acetone (200 ml), after the temperature is controlled to be between 45 and 50 ℃ and evenly stirred, acetone (50 ml) solution of 4-acetamido-5-chlorosalicylic acid methyl ester (24.37 g,0.10 mol) is slowly added dropwise, the reaction is continued until TLC detection reaction is complete, the reaction solution is poured into warm water (600 ml) with the temperature of between 45 and 50 ℃ and stirred and naturally cooled to room temperature, stirred and crystallized, filtered, and a filter cake is intermediate I-1 after toluene recrystallization, and the yield is 94.6The purity is 98.7 percent.
Example 7
1, 2-Dibromoethane (31.94 g,0.17 mol), na 2 CO 3 (10.60 g,0.10 mol) is added into acetonitrile (200 ml), after the temperature is controlled to be between 65 and 70 ℃ and stirred uniformly, acetonitrile (50 ml) solution of 4-acetamido-5-methyl chlorosalicylate (24.36 g,0.10 mol) is slowly added dropwise, the reaction is continued until TLC detection reaction is complete, the reaction solution is poured into warm water (600 ml) with the temperature of between 45 and 50 ℃ and stirred and cooled naturally to room temperature, stirred and crystallized, and filtered, and a filter cake is the intermediate I-1 after toluene recrystallization, the yield is 93.4 percent, and the purity is 99.0 percent.
Synthesis of I:
example 8
AlCl is added 3 (2.00 g,0.015 mol) is added into dry dichloromethane (150 ml), after the addition is stirred uniformly, 4-acetamido-2- (2-bromoethoxy) -5-chlorobenzoic acid methyl ester (I-1, 17.53g,0.05 mol) solution is added into dichloromethane (100 ml) at the temperature of 0-5 ℃, the temperature is continuously controlled to 20-25 ℃ until the reaction is finished, dilute hydrochloric acid (omega=5%, 50 ml) is added into the mixture at the temperature of-5 ℃ until the reaction is finished, an organic phase is separated, an aqueous phase is extracted by dichloromethane (20 ml multiplied by 3), the organic phase is combined, purified water (40 ml multiplied by 3) is washed, dried, filtered, filtrate is concentrated to be dry under reduced pressure, and petroleum ether/ethyl acetate (V) Petroleum ether :V Acetic acid ethyl ester Recrystallisation of the mixed solvent of =2:1) gives the compound methyl 4-acetamido-5-chloro-2, 3-dihydrobenzofuran-7-carboxylate in 91.5% yield and 99.3% purity.
Example 9
AlCl is added 3 (0.67 g,0.005 mol) into dry 1, 2-dichloroethane (150 ml), stirring, adding 1, 2-dichloroethane (100 ml) solution of methyl 4-acetamido-2- (2-bromoethoxy) -5-chlorobenzoate (17.50 g,0.05 mol) at 0-5deg.C, continuously controlling temperature to 25-30deg.C until the reaction is completed, adding dilute hydrochloric acid (ω=5%, 50 ml) at-5deg.C, separating to obtain organic phase, extracting water phase with dichloromethane (20 ml×3), mixing the organic phases, washing with purified water (40 ml×3), drying, filtering, concentrating the filtrate under reduced pressure to dryness, and concentrating the filtrate with petroleum ether/ethyl acetate (V) Petroleum ether :V Acetic acid ethyl ester Mixed solvent of =2:1)Recrystallizing to obtain the compound 4-acetamido-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid methyl ester with the yield of 89.3% and the purity of 99.0%.
Example 10
AlCl is added 3 (0.60 g,0.0045 mol) is added into dry nitromethane (150 ml), after the addition is uniformly stirred, 4-acetamido-2- (2-bromoethoxy) -5-chlorobenzoic acid methyl ester (17.55 g,0.05 mol) nitromethane (100 ml) solution is added at the temperature of 0-5 ℃, the temperature is continuously controlled at 15-20 ℃ until the reaction is finished, dilute hydrochloric acid (omega=5%, 50 ml) is added at the temperature of-5 ℃ until the reaction is finished, an organic phase is separated, an aqueous phase is extracted by dichloromethane (20 ml×3), the organic phase is combined, purified water (40 ml×3) is washed, dried and filtered, filtrate is decompressed and concentrated to dryness, and petroleum ether/ethyl acetate (V) is used Petroleum ether :V Acetic acid ethyl ester Recrystallisation of the mixed solvent of =2:1) gives the compound methyl 4-acetamido-5-chloro-2, 3-dihydrobenzofuran-7-carboxylate in 85.7% yield and 98.7% purity.
Example 11
AlCl is added 3 (6.67 g,0.05 mol) is added into dry carbon tetrachloride (150 ml), after the addition is uniformly stirred, 4-acetamido-2- (2-bromoethoxy) -5-chlorobenzoic acid methyl ester (17.54 g,0.05 mol) is added into carbon tetrachloride (100 ml) at the temperature of 0-5 ℃, the temperature is continuously controlled at 20-25 ℃ until the reaction is finished, dilute hydrochloric acid (omega=5%, 50 ml) is added at the temperature of-5 ℃ after the reaction is finished, an organic phase is separated, an aqueous phase is extracted by dichloromethane (20 ml multiplied by 3), the organic phase is combined, purified water (40 ml multiplied by 3) is washed, dried and filtered, filtrate is concentrated to dryness under reduced pressure, and petroleum ether/ethyl acetate (V) is used Petroleum ether :V Acetic acid ethyl ester Recrystallisation of the mixed solvent of =2:1) gives the compound methyl 4-acetamido-5-chloro-2, 3-dihydrobenzofuran-7-carboxylate in 90.1% yield and 98.1% purity.
Example 12
AlCl is added 3 (8.00 g,0.06 mol) is added into dry dichloromethane (150 ml), after the addition and stirring are carried out evenly, 4-acetamido-2- (2-bromoethoxy) -5-chlorobenzoic acid methyl ester (17.53 g,0.05 mol) dichloromethane (100 ml) solution is added at the temperature of 0-5 ℃, dilute hydrochloric acid is added at the temperature of-5 ℃ after the continuous temperature control is carried out at 20-25 ℃ until the reaction is finishedOmega = 5%,50 ml), separating the organic phase, extracting the aqueous phase with dichloromethane (20 ml x 3), combining the organic phases, washing with purified water (40 ml x 3), drying, filtering, concentrating the filtrate under reduced pressure to dryness, and concentrating the filtrate under reduced pressure with petroleum ether/ethyl acetate (V Petroleum ether :V Acetic acid ethyl ester Recrystallisation of the mixed solvent of =2:1) gives the compound methyl 4-acetamido-5-chloro-2, 3-dihydrobenzofuran-7-carboxylate in 87.4% yield and 97.8% purity.
Claims (8)
1. A process for preparing 4-acetamido-5-chloro-2, 3-dihydrobenzofuran-7-methyl carboxylate as the intermediate of prucalopride features that SM-1 is used as raw material, which is reacted with 1, 2-dibromoethane in organic solvent under the action of acid-binding agent to obtain intermediate I-1, which is used as catalyst AlCl 3 The compound 4-acetamido-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid methyl ester is prepared by catalytic reaction, and the reaction formula is as follows:
。
2. the preparation method according to claim 1, characterized by the specific steps of:
step 1, adding SM-1 and an acid binding agent into an organic solvent A, uniformly stirring at a controlled temperature, adding 1, 2-dibromoethane, continuing to react until TLC detection reaction is complete, and performing post-treatment to obtain an intermediate I-1; wherein the organic solvent A is selected fromN,NDimethylformamide (DMA),N,N-one or a combination of dimethylacetamide, acetonitrile and acetone;
step 2. AlCl is processed 3 Adding the compound I into an anhydrous organic solvent B, stirring uniformly after adding, adding a solution of an intermediate I-1 dissolved in a reaction solvent at a controlled temperature, heating to continue to react until TLC detection reaction is complete, and performing post-treatment to obtain the compound I; wherein the organic solvent B is selected from one or a combination of dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride, carbon disulfide, nitromethane and nitrobenzene.
3. The process according to claim 2, wherein the acid-binding agent in step 1 is selected from Na 2 CO 3 ，NaHCO 3 ，K 2 CO 3 ，KHCO 3 One or a combination thereof.
4. The preparation method according to claim 2, wherein the reaction molar ratio of SM-1 to 1, 2-dibromoethane in step 1 is 1.3-2.2.
5. The preparation method according to claim 2, wherein the reaction molar ratio of the SM-1 to the acid-binding agent in the step 1 is 1.0 to 1.5.
6. The method according to claim 2, wherein the temperature control in step 1 is 40-90 ℃.
7. The process according to claim 2, wherein in step 2 the I-1 is selected from AlCl 3 The feeding molar ratio of the catalyst is 1:0.1-1.0.
8. The preparation method according to claim 2, wherein the temperature control temperature in the step 2 is-5-10 ℃; the reaction temperature is 15-30 ℃.
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| CN104529960A (en) * | 2014-12-29 | 2015-04-22 | 成都百裕科技制药有限公司 | Preparation method of prucalopride intermediate |
| CN107337658A (en) * | 2016-05-03 | 2017-11-10 | 沈阳药科大学 | A kind of synthetic method of the chloro- 2,3- Dihydrobenzofuranes -7- carboxylic acids of butanedioic acid prucalopride intermediate 4- amino -5- |
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| WO2010127208A1 (en) * | 2009-04-30 | 2010-11-04 | Forest Laboratories Holdings Limited | Inhibitors of acetyl-coa carboxylase |
| CN104529960A (en) * | 2014-12-29 | 2015-04-22 | 成都百裕科技制药有限公司 | Preparation method of prucalopride intermediate |
| CN107337658A (en) * | 2016-05-03 | 2017-11-10 | 沈阳药科大学 | A kind of synthetic method of the chloro- 2,3- Dihydrobenzofuranes -7- carboxylic acids of butanedioic acid prucalopride intermediate 4- amino -5- |
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