CN114437007A - Preparation method of prucalopride intermediate - Google Patents
Preparation method of prucalopride intermediate Download PDFInfo
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- CN114437007A CN114437007A CN202011221689.2A CN202011221689A CN114437007A CN 114437007 A CN114437007 A CN 114437007A CN 202011221689 A CN202011221689 A CN 202011221689A CN 114437007 A CN114437007 A CN 114437007A
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- Prior art keywords
- reaction
- methyl ester
- acetamido
- acid methyl
- temperature
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- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 229960003863 prucalopride Drugs 0.000 title claims abstract description 14
- ZPMNHBXQOOVQJL-UHFFFAOYSA-N prucalopride Chemical compound C1CN(CCCOC)CCC1NC(=O)C1=CC(Cl)=C(N)C2=C1OCC2 ZPMNHBXQOOVQJL-UHFFFAOYSA-N 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 45
- 238000000034 method Methods 0.000 claims abstract description 32
- 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 21
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 9
- 239000003054 catalyst Substances 0.000 claims abstract description 7
- 230000009471 action Effects 0.000 claims abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 39
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 31
- 238000003756 stirring Methods 0.000 claims description 20
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium chloride Substances Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 238000001514 detection method Methods 0.000 claims description 11
- 239000003960 organic solvent Substances 0.000 claims description 11
- 238000002156 mixing Methods 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 8
- 239000011230 binding agent Substances 0.000 claims description 7
- 239000002994 raw material Substances 0.000 claims description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 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
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-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
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 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
- 239000002516 radical scavenger Substances 0.000 claims 1
- 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 abstract description 12
- 230000015572 biosynthetic process Effects 0.000 abstract description 9
- 238000003786 synthesis reaction Methods 0.000 abstract description 9
- 239000003814 drug Substances 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 5
- 239000007858 starting material Substances 0.000 abstract description 5
- 238000005804 alkylation reaction Methods 0.000 abstract description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 2
- 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 239000012074 organic phase Substances 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- 239000003208 petroleum Substances 0.000 description 12
- 238000001914 filtration Methods 0.000 description 11
- -1 formula II Chemical compound 0.000 description 11
- 230000008569 process Effects 0.000 description 11
- 239000012065 filter cake Substances 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- 239000012046 mixed solvent Substances 0.000 description 6
- 239000008213 purified water Substances 0.000 description 6
- 238000007363 ring formation reaction Methods 0.000 description 6
- 238000005660 chlorination reaction Methods 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 238000006722 reduction reaction Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000005406 washing Methods 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
- 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
- 239000003153 chemical reaction reagent Substances 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
- 239000012071 phase Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 230000009467 reduction Effects 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
- 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
- 230000003321 amplification Effects 0.000 description 2
- 239000008346 aqueous phase Substances 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
- 238000006555 catalytic reaction Methods 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005695 dehalogenation reaction Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 231100000086 high toxicity Toxicity 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
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-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
- 238000003541 multi-stage reaction Methods 0.000 description 2
- 238000003199 nucleic acid amplification method 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
- 238000000926 separation method 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
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-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
- 238000003309 Hoesch reaction Methods 0.000 description 1
- 238000006751 Mitsunobu reaction Methods 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
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-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
- 238000007112 amidation reaction Methods 0.000 description 1
- 229960004909 aminosalicylic acid Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 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
- 230000000694 effects Effects 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
- 231100000171 higher toxicity Toxicity 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
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000007788 liquid Substances 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
- 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 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
- 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
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000035484 reaction time 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
- 238000013341 scale-up Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride 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
- 150000003459 sulfonic acid esters Chemical class 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
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 238000006227 trimethylsilylation reaction Methods 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
Landscapes
- 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 drug 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 takes 4-acetamido-5-chlorosalicylic acid methyl ester as a starting material, firstly reacts with 1, 2-dibromoethane, and then directly constructs a benzotetrahydrofuran ring through alkylation reaction on a benzene ring under the action of a catalyst to prepare a compound I, wherein the reaction equation is as follows. The preparation method can effectively shorten the reaction route, improve the operation safety, and the target product prepared by the method has higher yield and purity.
Description
Technical Field
The invention belongs to the technical field of drug 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
Praecopril Succinate (Prucalopride Succinate) with chemical name of 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 Movetis, Belgium4) Receptor agonists, which restore impaired intestinal motility through direct action on the intestinal wall. The European Union of 10 months in 2009 approved for treating chronic constipation, 1 month in 2010 on Germany, 3 months in the same year on British, and 10 months in 2012 on FDA approval, clinical studies show that the drug has constant curative effect and safety on patients with severe chronic constipation, and the chemical structural formula is as follows:
at present, a plurality of methods are disclosed for preparing prucalopride, wherein most of the methods (such as the synthesis of prucalopride, pharmaceutical and clinical research, 2011, Aug; 19(4):306-307, patent CN1164233A (CN1071332C), CN103664912B and the like) relate to the synthesis of 4-amino-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid, namely the formula II, and then the intermediate II and 1- (3-methoxypropyl) -4-piperidinamine are subjected to amidation reaction to prepare the final product prucalopride.
From the above, it is known that 4-amino-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid, i.e. formula II, as a key intermediate for the preparation of prucalopride directly affects the production, market supply and quality problems of the drug. The related chemical structural formula is as follows:
currently, the following methods are mainly used for the synthesis of 4-amino-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid:
patent US5374637(CN1045781, EP389037) and document J.het.chem.,1980,17(6):1333-1335 starting from m-methoxyaniline protected by pivaloyl, hydroxyethylated, cyclized, chlorinated, brominated under the action of butyllithium and finally reacted with carbon dioxide under the action of butyllithium, with a yield of about 18%, using butyllithium and gaseous reaction substances (ethylene oxide, carbon dioxide) twice, requiring a low-temperature heterogeneous reaction at-78 ℃, and whose hexane solution is flammable, relatively expensive, and the isomers produced by chlorination requiring column chromatography separation, which is not suitable for industrial scale-up.
Synthesis, pharmaceutical and pharmaceutical use of chem. pharm. Bull, 1998,46(1),42-52 and prucaloprideClinical research, 2011, (4),306-4/NaIO4Oxidation reaction, NaBH4Reduction reaction, Mitsunobu reaction retaining ring, chlorination reaction and hydrolysis reaction to obtain the target product. However, the oxidation step of the synthetic route needs to use a highly toxic and expensive osmium tetroxide reagent, and the cyclization step uses toxic triphenylphosphine, so that the product needs to be purified by column chromatography, and the yield is low, thus the synthetic route is not suitable for industrial large-scale production.
Patent CN103012337A improves the above process, and uses ozone instead of osmium tetroxide for oxidation, and introduces sulfonic acid ester as leaving group before cyclization reaction, but the method has long steps, complicated operation, expensive starting compound, difficult to obtain, and needs to use alkyl sulfonyl chloride with corrosiveness, irritation and genotoxicity, and the overall yield is low, and is difficult to be produced industrially in large scale.
The patent CN102942542A adopts the same strategy to prepare a target product, ruthenium trichloride or a hydrate thereof/periodate composite catalyst is oxidized to prepare aldehyde group, and halogen, p-toluene sulfonyloxy, trifluoromethyl sulfonyloxy, methylsulfonyloxy or phenylsulfonyloxy is taken as a leaving group before cyclization reaction.
The patent CN104529960A adopts 4-amino-2-hydroxybenzoic acid methyl ester as an initial material, firstly uses trifluoroacetyl group to protect amino, then introduces chloroacetyl through Friedel-Crafts acylation reaction, and then sequentially carries out cyclization, reduction, chlorination, hydrolysis and other reactions to prepare the target product. However, the process adopts trifluoroacetic anhydride with higher price to introduce a protective group, and simultaneously adopts Raney Ni with higher toxicity and danger as a catalyst, so that the industrial amplification production is difficult.
The patent CN106316998A improves the above process, and the process uses 2-methoxy-4-acetamido-5-chlorobenzoic acid methyl ester as starting material to prepare the target product. However, the operation danger is high due to the adoption of a highly toxic substance hydrazine hydrate for reduction, and ester bonds and amido bonds in a substrate structure are extremely easy to aminolyze due to the strong alkalinity of the hydrazine hydrate, so that the method does not have amplification conditions.
Chemical Process Research, Vol.870, Chapter 8, Washington, American Chemical Society,2003, 125-Buchner 139 was prepared from methyl 4-acetamido-5-chlorosalicylate (methyl 4-acetamido-2-hydroxy-5-chlorobenzoate) by bromination, bromoethylation, cyclization and hydrolysis, with mild reaction conditions and a yield of 29%. The process has more problems in the final hydrolysis reaction, such as: 1. the hydrolysis reaction time is long and needs more than 15 hours, and the raw materials are not completely reacted; 2. the substrate (4-acetamido-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid methyl ester) prepared by the literature method has poor purity, and 2 protecting groups are directly hydrolyzed without purification to generate a lot of impurities, so that the quality of a target product is difficult to guarantee, and the purification difficulty is increased, thereby influencing the final product to reach the drug standard.
The patent CN107337658A and the literature prucalopride succinate are synthesized, and the target product is prepared by taking p-aminosalicylic acid as a starting material through multi-step reactions in the journals of chinese medical industry, 2012,43(1), 5-8. However, the process adopts bromine for bromination reaction, has high toxicity, simultaneously adopts sulfonyl chloride with strong corrosivity for chlorination reaction, and uses a large amount of zinc powder to cause serious pollution.
The research on the synthesis process of the key intermediate 4-amino-5-chloro-2, 3-dihydro-7-benzofuran benzoic acid of pruricapride in the literature, 2016,25(2),38-40 in the Chinese pharmaceutical industry, takes 2-methoxy-4-acetamido-5-chlorobenzoic acid methyl ester as a starting material, and prepares a target product through multi-step reactions. The process adopts the bromine with high toxicity for bromination and adopts the sodium metal for dehalogenation coupling, so that the steps are prolonged and the production is difficult to enlarge.
The document Synlett,1993, (4) 269-270 is prepared by using 4-acetamido-2-hydroxybenzoic acid methyl ester as a raw material, cyclizing the raw material through chlorination, iodination and trimethylsilylation, and finally hydrolyzing the raw material under the catalysis of rhodium to reduce the product, wherein the total yield is 38%. Expensive silicon reagent and rhodium reagent are used in the route, and the method is not suitable for mass production.
In J.Am.chem.Soc.,1978,100(15), 4842-4852 uses methyl 2-methoxy-4-amino-5-chlorobenzoate as raw material and undergoes Houben-Hoesch reaction, cyclization, reduction and hydrolysis reaction to obtain the target product. The literature reports no yield, and the reduction reaction also uses an expensive rhodium catalyst.
From the above, it can be known that the existing preparation method of 4-amino-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid has many problems, and most processes prepare 4-acetamido-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid methyl ester through various ways and then hydrolyze the 4-acetamido-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid methyl ester 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 the production, market supply and quality problems of the medicine are directly influenced.
In view of the defects existing in the prior art for preparing 4-acetamido-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid methyl ester, the research and search for a preparation process which is simple and convenient to operate, mild in reaction conditions, 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 still needs to be solved at present.
Disclosure of Invention
Aiming at the 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:
a preparation method of a prucalopride intermediate 4-acetamido-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid methyl ester comprises the following steps of taking 4-acetamido-5-chlorosalicylic acid methyl ester (4-acetamido-2-hydroxy-5-chlorobenzoic acid methyl ester), namely SM-1, as a reaction raw material, reacting with 1, 2-dibromoethane in an organic solvent under the action of an acid binding agent to obtain an intermediate I-1, and carrying out catalytic reaction on the intermediate I-1 by using a catalyst to obtain a compound 4-acetamido-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid methyl ester, wherein the reaction formula is as follows:
a preparation method of prucalopride intermediate 4-acetamido-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid methyl ester shown as a 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, slowly dripping 1, 2-dibromoethane after uniformly stirring at controlled temperature, continuing to react until TLC detection reaction is complete, and performing aftertreatment to obtain an intermediate I-1;
step 2, mixing AlCl3Adding the mixture into an anhydrous organic solvent B, uniformly stirring after adding, adding an anhydrous organic solvent B solution of the intermediate I-1 at a controlled temperature, heating, continuously reacting until the TLC detection reaction is complete, and carrying out post-treatment to obtain a compound I.
Preferably, the acid-binding agent in step 1 is selected from Na2CO3，NaHCO3，K2CO3，KHCO3One or a combination thereof, preferably Na2CO3。
Preferably, the organic solvent A in the step 1 is selected from one or a combination of N, N-dimethylformamide, N-dimethylacetamide, acetonitrile and acetone, and is preferably N, N-dimethylformamide.
Preferably, the reaction molar ratio of the SM-1 to the acid-binding agent in the step 1 is 1: 1.0-1.5, preferably 1: 1.2.
Preferably, the reaction molar ratio of SM-1 to 1, 2-dibromoethane in the step 1 is 1: 1.3-2.2, preferably 1: 1.7.
Preferably, the reaction temperature in the step 1 is 40-90 ℃, preferably 50-55 ℃.
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 the step 2 is selected from one or a combination of dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride, carbon disulfide, nitromethane and nitrobenzene, and dichloromethane is preferred.
Preferably, step 2 is performed by reacting I-1 with AlCl3The feeding molar ratio of (3) is 1: 0.1-1.0, preferably 1: 0.3.
Preferably, the temperature controlled when the I-1 solution is added in the step 2 is-5-10 ℃; the reaction temperature is 15-30 ℃, preferably 20-25 ℃.
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 water phase with dichloromethane, mixing organic phases, washing with purified water, drying, filtering, concentrating the filtrate under reduced pressure to dryness, and adding petroleum ether/ethyl acetate (V)Petroleum ether:VEthyl acetateRecrystallizing 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, convenient and efficient method for preparing prucalopride intermediate 4-acetamido-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid methyl ester. The invention adopts AlCl3As a catalyst, the method directly performs alkylation reaction on a benzene ring to construct a benzotetrahydrofuran ring, can effectively shorten a reaction route and is safer to operate compared with a dehalogenation coupling method in the prior art and a method of performing acylation reaction by using chloroacetyl chloride and then reducing. The whole synthesis method is simple to operate, and the prepared target product is high in yield and purity and suitable for industrial production.
Detailed Description
The invention is further illustrated by the following examples, which should be properly understood: the examples of the present invention are merely illustrative and not restrictive, and therefore, the present invention may be modified in a simple manner without departing from the scope of the invention as claimed.
In the following examples, various procedures and methods not described in detail are conventional methods well known in the art.
Synthesis of I-1:
example 1
1, 2-dibromoethane (31.94g, 0.17mol), Na2CO3(12.72g, 0.12mol) is added into N, N-dimethylformamide (200ml), the temperature is controlled to be 50-55 ℃, after the mixture is evenly stirred, 4-acetamido-5-chlorosalicylic acid methyl ester (4-acetamido-2-hydroxy-5-chlorobenzoic acid methyl ester, SM-1, 24.36g, 0.10 g) is slowly drippedmol) of N, N-dimethylformamide (50ml), continuously reacting until the TLC detection reaction is complete, pouring the reaction solution into warm water (600ml) at the temperature of 45-50 ℃, stirring and naturally cooling to room temperature, stirring for crystallization, filtering, and recrystallizing a filter cake with toluene to obtain an intermediate I-1, wherein the yield is 95.7%, and the purity is 99.0%.
Example 2
1, 2-dibromoethane (41.33g, 0.22mol), KHCO3Adding (12.01g, 0.12mol) into N, N-dimethylformamide (200ml), controlling the temperature to be 50-55 ℃, uniformly stirring, slowly dropwise adding a N, N-dimethylformamide (50ml) solution of 4-acetamido-5-chlorosalicylic acid methyl ester (24.35g, 0.10mol), continuously reacting until the TLC detection reaction is complete, pouring the reaction solution into warm water (600ml) at 45-50 ℃, stirring and naturally cooling to room temperature, stirring for crystallization, filtering, and recrystallizing a filter cake with toluene to obtain an intermediate I-1, wherein the yield is 94.4%, and the purity is 97.3%.
Example 3
1, 2-dibromoethane (43.21g, 0.23mol), K2CO3Adding (16.58g, 0.12mol) into N, N-dimethylformamide (200ml), controlling the temperature to be 50-55 ℃, uniformly stirring, slowly dropwise adding a N, N-dimethylformamide (50ml) solution of 4-acetamido-5-chlorosalicylic acid methyl ester (24.38g, 0.10mol), continuously reacting until the TLC detection reaction is complete, pouring the reaction solution into warm water (600ml) at 45-50 ℃, stirring and naturally cooling to room temperature, stirring for crystallization, filtering, and recrystallizing a filter cake with toluene to obtain an intermediate I-1, wherein the yield is 90.1%, and the purity is 97.1%.
Example 4
1, 2-dibromoethane (24.42g, 0.13mol), NaHCO3(10.08g, 0.12mol) is added into N, N-dimethylacetamide (200ml), the temperature is controlled to be 60-65 ℃ and stirred uniformly, then N, N-dimethylacetamide (50ml) solution of 4-acetamido-5-chlorosalicylic acid methyl ester (24.36g, 0.10mol) is slowly dripped in until TLC detection reaction is complete, the reaction solution is poured into warm water (600ml) at 45-50 ℃ and stirred and naturally cooled to room temperature, stirred for crystallization, filtered, and a filter cake is recrystallized by toluene to obtain an intermediate I-1, the yield is 93.5%, and the purity is 98.8%.
Example 5
1, 2-twoBromoethane (22.54g, 0.12mol), Na2CO3(12.72g, 0.12mol) is added into N, N-dimethylformamide (200ml), the temperature is controlled to be 50-55 ℃, after stirring uniformly, N-dimethylformamide (50ml) solution of 4-acetamido-5-chlorosalicylic acid methyl ester (24.34g, 0.10mol) is slowly dripped, the reaction is continued until the TLC detection reaction is complete, the reaction solution is poured into warm water (600ml) at the temperature of 45-50 ℃, stirred and naturally cooled to room temperature, stirred and crystallized, filtered, and a filter cake is recrystallized by toluene to obtain an intermediate I-1, the yield is 89.7%, and the purity is 99.1%.
Example 6
1, 2-dibromoethane (31.94g, 0.17mol), Na2CO3(15.90g, 0.15mol) is added into acetone (200ml), after the temperature is controlled to 45-50 ℃ and the mixture is uniformly stirred, acetone (50ml) solution of 4-acetamido-5-chlorosalicylic acid methyl ester (24.37g, 0.10mol) is slowly dripped into the mixture to continue to react until the TLC detection reaction is complete, the reaction solution is poured into warm water (600ml) with the temperature of 45-50 ℃ and stirred and naturally cooled to the room temperature, the mixture is stirred and crystallized, filtered, and a filter cake is recrystallized by toluene to obtain an intermediate I-1, wherein the yield is 94.6 percent, and the purity is 98.7 percent.
Example 7
1, 2-dibromoethane (31.94g, 0.17mol), Na2CO3Adding (10.60g, 0.10mol) into acetonitrile (200ml), controlling the temperature to be 65-70 ℃, stirring uniformly, slowly dropwise adding acetonitrile (50ml) solution of 4-acetamido-5-chlorosalicylic acid methyl ester (24.36g, 0.10mol), continuing to react until the TLC detection reaction is complete, pouring the reaction solution into warm water (600ml) at 45-50 ℃, stirring and naturally cooling to room temperature, stirring for crystallization, filtering, recrystallizing a filter cake by toluene to obtain the intermediate I-1, wherein the yield is 93.4%, and the purity is 99.0%.
I synthesis:
example 8
Mixing AlCl3(2.00g, 0.015mol) is added into dry dichloromethane (150ml), after the addition is finished and the mixture is evenly stirred, dichloromethane (100ml) solution of 4-acetamido-2- (2-bromoethoxy) -5-chlorobenzoic acid methyl ester (I-1, 17.53g, 0.05mol) is added at the temperature of 0-5 ℃, the temperature is continuously controlled at 20-25 ℃ until the reaction is finished, dilute hydrochloric acid (omega is 5 percent and 50ml) is added at the temperature of-5 ℃, organic phase is separated, and the aqueous phase is dichloroExtracting with methane (20ml × 3), mixing organic phases, washing with purified water (40ml × 3), drying, filtering, concentrating the filtrate under reduced pressure to dryness, and adding petroleum ether/ethyl acetate (V)Petroleum ether:VEthyl acetateThe compound 4-acetylamino-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid methyl ester was obtained by recrystallization from a mixed solvent of 2:1) in a yield of 91.5% and a purity of 99.3%.
Example 9
Mixing AlCl3(0.67g, 0.005mol) is added into dry 1, 2-dichloroethane (150ml), after the addition is uniformly stirred, a 1, 2-dichloroethane (100ml) solution of 4-acetamido-2- (2-bromoethoxy) -5-chlorobenzoic acid methyl ester (17.50g, 0.05mol) is added at the temperature of 0-5 ℃, the temperature is controlled to be 25-30 ℃ continuously until the reaction is finished, dilute hydrochloric acid (omega is 5%, 50ml) is added at the temperature of-5 ℃, liquid separation is carried out to obtain an organic phase, a water phase is extracted by dichloromethane (20ml multiplied by 3), the organic phase is combined, purified water (40ml multiplied by 3) is washed, drying and filtration are carried out, the filtrate is decompressed and concentrated to be dry, and petroleum ether/ethyl acetate (V multiplied by 3) is usedPetroleum ether:VEthyl acetateThe mixed solvent of 2:1) was recrystallized to obtain 4-acetylamino-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid methyl ester, yield 89.3%, purity 99.0%.
Example 10
Mixing AlCl3(0.60g, 0.0045mol) is added into dry nitromethane (150ml), after the addition is finished and the mixture is uniformly stirred, a nitromethane (100ml) solution of 4-acetamido-2- (2-bromoethoxy) -5-chlorobenzoic acid methyl ester (17.55g, 0.05mol) 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 is 5 percent and 50ml) is added at the temperature of-5 ℃, the organic phase is separated and extracted by dichloromethane (20ml multiplied by 3), the organic phase is combined, purified water (40ml multiplied by 3) is used for washing, drying and filtering are carried out, the filtrate is decompressed and concentrated to be dry, and petroleum ether/ethyl acetate (V) is used for extracting the organic phase by dichloromethane (20ml multiplied by 3), and then the organic phase is driedPetroleum ether:VEthyl acetateThe compound 4-acetylamino-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid methyl ester was obtained by recrystallization from a mixed solvent of 2:1), yield 85.7% and purity 98.7%.
Example 11
Mixing AlCl3(6.67g, 0.05mol) was added to dry carbon tetrachloride (150ml)After the addition, uniformly stirring, adding a carbon tetrachloride (100ml) solution of 4-acetamido-2- (2-bromoethoxy) -5-chlorobenzoic acid methyl ester (17.54g, 0.05mol) at the temperature of 0-5 ℃, continuously controlling the temperature to be 20-25 ℃ until the reaction is finished, adding dilute hydrochloric acid (omega-5%, 50ml) at the temperature of-5 ℃, separating to obtain an organic phase, extracting a water phase with dichloromethane (20ml multiplied by 3), combining the organic phases, washing with purified water (40ml multiplied by 3), drying, filtering, concentrating the filtrate under reduced pressure to dryness, and adding petroleum ether/ethyl acetate (V)Petroleum ether:VEthyl acetateThe mixed solvent of 2:1) was recrystallized to obtain 4-acetylamino-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid methyl ester, yield 90.1%, purity 98.1%.
Example 12
Mixing AlCl3Adding (8.00g, 0.06mol) into dried dichloromethane (150ml), stirring uniformly after adding, controlling the temperature to be 0-5 ℃, adding a dichloromethane (100ml) solution of 4-acetamido-2- (2-bromoethoxy) -5-chlorobenzoic acid methyl ester (17.53g, 0.05mol), controlling the temperature to be 20-25 ℃ continuously until the reaction is finished, controlling the temperature to be-5 ℃, adding dilute hydrochloric acid (omega-5%, 50ml), separating, taking an organic phase, extracting an aqueous phase with dichloromethane (20ml multiplied by 3), combining the organic phases, washing with purified water (40ml multiplied by 3), drying, filtering, concentrating a filtrate under reduced pressure to be dry, and adding petroleum ether/ethyl acetate (V) into the filtratePetroleum ether:VEthyl acetateThe compound 4-acetylamino-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid methyl ester was obtained by recrystallization from a mixed solvent of 2:1) in 87.4% yield and 97.8% purity.
Claims (10)
1. A preparation method of prucalopride intermediate 4-acetamido-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid methyl ester is characterized in that 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, and the intermediate I-1 is catalyzed by a catalyst to prepare a compound 4-acetamido-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid methyl ester, wherein the reaction formula is as follows:
2. the preparation method according to claim 1, comprising the following steps:
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, continuously reacting until TLC detection reaction is complete, and performing post-treatment to obtain an intermediate I-1;
step 2, mixing AlCl3Adding the mixture into an anhydrous organic solvent B, uniformly stirring after adding, adding a solution of the intermediate I-1 dissolved in a reaction solvent at a controlled temperature, heating, continuously reacting until the TLC detection reaction is complete, and carrying out post-treatment to obtain a compound I.
3. The method of claim 2, wherein the acid scavenger used in step 1 is selected from Na2CO3，NaHCO3，K2CO3，KHCO3One or a combination thereof.
4. The method according to claim 2, wherein the organic solvent A in step 1 is one or a combination of N, N-dimethylformamide, N-dimethylacetamide, acetonitrile and acetone.
5. The preparation method according to claim 2, wherein the reaction molar ratio of the SM-1 to the 1, 2-dibromoethane in the step 1 is 1: 1.3-2.2.
6. The preparation method according to claim 2, wherein the molar ratio of SM-1 to the acid-binding agent in step 1 is 1: 1.0-1.5.
7. The method according to claim 2, wherein the reaction temperature in step 1 is 40 to 90 ℃.
8. The method according to claim 2, wherein 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 and nitrobenzene.
9. The method of claim 2, wherein step 2 comprises reacting I-1 with AlCl3The feeding molar ratio of (A) to (B) is 1: 0.1-1.0.
10. The method according to claim 2, wherein the temperature of the solution I-1 added in step 2 is controlled to be-5 to 10 ℃; the reaction temperature is 15-30 ℃.
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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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| 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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| CN115745929A (en) * | 2022-11-07 | 2023-03-07 | 山东四环药业股份有限公司 | Preparation method of prankari succinate key intermediate |
| CN115745929B (en) * | 2022-11-07 | 2024-01-19 | 山东四环药业股份有限公司 | Preparation method of prizepine succinate key intermediate |
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