CN115894330A - Synthesis method and application of 1-acetyl-1H-indol-3-yl acetate derivative - Google Patents
Synthesis method and application of 1-acetyl-1H-indol-3-yl acetate derivative Download PDFInfo
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- CN115894330A CN115894330A CN202211081997.9A CN202211081997A CN115894330A CN 115894330 A CN115894330 A CN 115894330A CN 202211081997 A CN202211081997 A CN 202211081997A CN 115894330 A CN115894330 A CN 115894330A
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- DNVFBLDIZKYQPL-UHFFFAOYSA-N (1-acetylindol-3-yl) acetate Chemical class C1=CC=C2C(OC(=O)C)=CN(C(C)=O)C2=C1 DNVFBLDIZKYQPL-UHFFFAOYSA-N 0.000 title claims abstract description 29
- 238000001308 synthesis method Methods 0.000 title claims abstract description 15
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims abstract description 132
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims abstract description 50
- 239000004471 Glycine Substances 0.000 claims abstract description 25
- 239000003288 aldose reductase inhibitor Substances 0.000 claims abstract description 13
- 150000001558 benzoic acid derivatives Chemical class 0.000 claims abstract description 11
- 239000003814 drug Substances 0.000 claims abstract description 11
- 229910052751 metal Inorganic materials 0.000 claims abstract description 11
- 239000002184 metal Substances 0.000 claims abstract description 11
- 150000007530 organic bases Chemical class 0.000 claims abstract description 11
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims abstract description 10
- 208000033679 diabetic kidney disease Diseases 0.000 claims abstract description 10
- 239000002904 solvent Substances 0.000 claims abstract description 10
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 4
- 238000004519 manufacturing process Methods 0.000 claims abstract description 4
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 77
- 238000006243 chemical reaction Methods 0.000 claims description 60
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 58
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 51
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 51
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 29
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 17
- 238000005917 acylation reaction Methods 0.000 claims description 16
- 238000007363 ring formation reaction Methods 0.000 claims description 16
- 239000000243 solution Substances 0.000 claims description 13
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 9
- 239000000843 powder Substances 0.000 claims description 9
- 239000012670 alkaline solution Substances 0.000 claims description 8
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 7
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- IKCLCGXPQILATA-UHFFFAOYSA-N 2-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Cl IKCLCGXPQILATA-UHFFFAOYSA-N 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- 238000010189 synthetic method Methods 0.000 claims description 5
- HQLOEBRPCVIFCT-UHFFFAOYSA-N 2,6-dibromobenzoic acid Chemical compound OC(=O)C1=C(Br)C=CC=C1Br HQLOEBRPCVIFCT-UHFFFAOYSA-N 0.000 claims description 4
- MRUDNSFOFOQZDA-UHFFFAOYSA-N 2,6-dichlorobenzoic acid Chemical compound OC(=O)C1=C(Cl)C=CC=C1Cl MRUDNSFOFOQZDA-UHFFFAOYSA-N 0.000 claims description 4
- ONOTYLMNTZNAQZ-UHFFFAOYSA-N 2,6-difluorobenzoic acid Chemical compound OC(=O)C1=C(F)C=CC=C1F ONOTYLMNTZNAQZ-UHFFFAOYSA-N 0.000 claims description 4
- NSTREUWFTAOOKS-UHFFFAOYSA-N 2-fluorobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1F NSTREUWFTAOOKS-UHFFFAOYSA-N 0.000 claims description 4
- 229940118148 Aldose reductase inhibitor Drugs 0.000 claims description 4
- MNQZXJOMYWMBOU-UHFFFAOYSA-N glyceraldehyde Chemical compound OCC(O)C=O MNQZXJOMYWMBOU-UHFFFAOYSA-N 0.000 claims description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 4
- XRXMNWGCKISMOH-UHFFFAOYSA-N 2-bromobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Br XRXMNWGCKISMOH-UHFFFAOYSA-N 0.000 claims description 3
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 3
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 55
- 229940090865 aldose reductase inhibitors used in diabetes Drugs 0.000 abstract description 9
- 239000002994 raw material Substances 0.000 abstract description 9
- 229940079593 drug Drugs 0.000 abstract description 8
- 238000002360 preparation method Methods 0.000 abstract description 8
- 230000008901 benefit Effects 0.000 abstract description 4
- 239000012043 crude product Substances 0.000 abstract description 4
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- 238000006555 catalytic reaction Methods 0.000 abstract description 3
- 238000005815 base catalysis Methods 0.000 abstract description 2
- 238000006798 ring closing metathesis reaction Methods 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 238000003756 stirring Methods 0.000 description 54
- 239000000047 product Substances 0.000 description 42
- -1 1-acetyl-4-fluoroindole-3-acetic acid Chemical compound 0.000 description 37
- 239000000203 mixture Substances 0.000 description 35
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 30
- 238000001035 drying Methods 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 13
- 239000012141 concentrate Substances 0.000 description 13
- 238000001914 filtration Methods 0.000 description 13
- 239000007787 solid Substances 0.000 description 13
- 239000000725 suspension Substances 0.000 description 13
- 239000007864 aqueous solution Substances 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000008187 granular material Substances 0.000 description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 5
- 239000008103 glucose Substances 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 230000006907 apoptotic process Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 238000007873 sieving Methods 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 238000012258 culturing Methods 0.000 description 3
- CHNUOJQWGUIOLD-NFZZJPOKSA-N epalrestat Chemical compound C=1C=CC=CC=1\C=C(/C)\C=C1/SC(=S)N(CC(O)=O)C1=O CHNUOJQWGUIOLD-NFZZJPOKSA-N 0.000 description 3
- 229950010170 epalrestat Drugs 0.000 description 3
- CHNUOJQWGUIOLD-UHFFFAOYSA-N epalrestate Natural products C=1C=CC=CC=1C=C(C)C=C1SC(=S)N(CC(O)=O)C1=O CHNUOJQWGUIOLD-UHFFFAOYSA-N 0.000 description 3
- 238000011049 filling Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- ATCRIUVQKHMXSH-UHFFFAOYSA-N 2,4-dichlorobenzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C=C1Cl ATCRIUVQKHMXSH-UHFFFAOYSA-N 0.000 description 2
- SYTRADHUGVPQHX-UHFFFAOYSA-N 2-(1-acetyl-5-bromoindol-3-yl)acetic acid Chemical compound BrC1=CC=C2N(C(=O)C)C=C(CC(O)=O)C2=C1 SYTRADHUGVPQHX-UHFFFAOYSA-N 0.000 description 2
- RRSNDVCODIMOFX-MPKOGUQCSA-N Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O Chemical compound Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O RRSNDVCODIMOFX-MPKOGUQCSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 210000003584 mesangial cell Anatomy 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 229940100691 oral capsule Drugs 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000007039 two-step reaction Methods 0.000 description 2
- YNVNFMCYBIBHLH-UHFFFAOYSA-N 2,3-dibromobenzoic acid Chemical compound OC(=O)C1=CC=CC(Br)=C1Br YNVNFMCYBIBHLH-UHFFFAOYSA-N 0.000 description 1
- QAOJBHRZQQDFHA-UHFFFAOYSA-N 2,3-dichlorobenzoic acid Chemical compound OC(=O)C1=CC=CC(Cl)=C1Cl QAOJBHRZQQDFHA-UHFFFAOYSA-N 0.000 description 1
- JLZVIWSFUPLSOR-UHFFFAOYSA-N 2,3-difluorobenzoic acid Chemical compound OC(=O)C1=CC=CC(F)=C1F JLZVIWSFUPLSOR-UHFFFAOYSA-N 0.000 description 1
- NAGGYODWMPFKJQ-UHFFFAOYSA-N 2,4-dibromobenzoic acid Chemical compound OC(=O)C1=CC=C(Br)C=C1Br NAGGYODWMPFKJQ-UHFFFAOYSA-N 0.000 description 1
- NJYBIFYEWYWYAN-UHFFFAOYSA-N 2,4-difluorobenzoic acid Chemical compound OC(=O)C1=CC=C(F)C=C1F NJYBIFYEWYWYAN-UHFFFAOYSA-N 0.000 description 1
- SQQKOTVDGCJJKI-UHFFFAOYSA-N 2,5-dibromobenzoic acid Chemical compound OC(=O)C1=CC(Br)=CC=C1Br SQQKOTVDGCJJKI-UHFFFAOYSA-N 0.000 description 1
- QVTQYSFCFOGITD-UHFFFAOYSA-N 2,5-dichlorobenzoic acid Chemical compound OC(=O)C1=CC(Cl)=CC=C1Cl QVTQYSFCFOGITD-UHFFFAOYSA-N 0.000 description 1
- LBQMIAVIGLLBGW-UHFFFAOYSA-N 2,5-difluorobenzoic acid Chemical compound OC(=O)C1=CC(F)=CC=C1F LBQMIAVIGLLBGW-UHFFFAOYSA-N 0.000 description 1
- 102000016912 Aldehyde Reductase Human genes 0.000 description 1
- 108010053754 Aldehyde reductase Proteins 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- ACFIXJIJDZMPPO-NNYOXOHSSA-N NADPH Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](OP(O)(O)=O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 ACFIXJIJDZMPPO-NNYOXOHSSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 208000037887 cell injury Diseases 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- INHCSSUBVCNVSK-UHFFFAOYSA-L lithium sulfate Inorganic materials [Li+].[Li+].[O-]S([O-])(=O)=O INHCSSUBVCNVSK-UHFFFAOYSA-L 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- 229940096978 oral tablet Drugs 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- RBTVSNLYYIMMKS-UHFFFAOYSA-N tert-butyl 3-aminoazetidine-1-carboxylate;hydrochloride Chemical compound Cl.CC(C)(C)OC(=O)N1CC(N)C1 RBTVSNLYYIMMKS-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
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Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention provides a synthesis method and application of a 1-acetyl-1H-indol-3-yl acetate derivative, belonging to the technical field of chemical drug synthesis. The invention takes halogenated benzoic acid as raw material, reacts with glycine under the alkaline condition through metal catalysis, then acidylates with acetic anhydride under the alkaline condition, finally prepares a crude product with the acetic anhydride through organic base catalysis ring closure, and the crude product is recrystallized in an alcohol solvent to prepare the 1-acetyl-1H-indol-3-yl acetate derivative; the derivatives are useful as aldose reductase inhibitors and for the preparation of candidate drug molecules for the treatment of diabetic nephropathy. The synthesis method has the advantages of simple operation, easily obtained raw materials, high yield, high purity and low cost, and is beneficial to mass production.
Description
Technical Field
The invention relates to the technical field of chemical drug synthesis, in particular to a synthesis method and application of a 1-acetyl-1H-indol-3-yl acetate derivative.
Background
Diabetic Nephropathy (DN) is one of the chronic complications of microvasculature, an important complication of diabetic patients, and has great health risks. Aldose Reductase Inhibitors (ARI) have been the first choice of drugs for the treatment of diabetic nephropathy.
In recent years, a variety of novel ARI have been reported for the treatment of diabetic nephropathy, but few and few have been evaluated clinically, and the inhibitory activity of existing aldose reductase inhibitors is not high. Therefore, how to continuously discover some new compound molecules as novel aldose reductase inhibitors is necessary for preparing candidate drug molecules for treating diabetic nephropathy.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a synthetic method and application of a 1-acetyl-1H-indol-3-yl acetate derivative.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a synthetic method of a 1-acetyl-1H-indole-3-yl acetate derivative, which comprises the following steps:
wherein R is H, F, cl or Br;
the method comprises the following steps:
1) Reacting halogenated benzoic acid with glycine under the action of carbonate and metal powder to obtain a compound b;
2) Performing acylation reaction on the compound b and acetic anhydride under an alkaline condition to obtain a compound c;
3) Carrying out a cyclization reaction on the compound c and acetic anhydride under the action of organic base to obtain a 1-acetyl-1H-indol-3-yl acetate derivative;
the structural general formula of the 1-acetyl-1H-indole-3-yl acetate derivative is as follows:
wherein R is H, F, cl or Br.
Further, the halogenated benzoic acid comprises one or more of o-fluorobenzoic acid, o-chlorobenzoic acid, o-bromobenzoic acid, 2, 6-difluorobenzoic acid, 2, 6-dichlorobenzoic acid and 2, 6-dibromobenzoic acid.
Further, the reaction of step 1) is carried out in a solvent comprising dimethylformamide and/or diisopropylethylamine.
Further, the carbonate comprises one or more of lithium carbonate, sodium carbonate and potassium carbonate; the metal powder comprises copper powder and/or iron powder; the molar ratio of the halogenated benzoic acid to the glycine to the carbonate to the metal powder is 0.1:0.1 to 0.2:0.1 to 0.2:0.01 to 0.3.
Further, the molar volume ratio of the glycine to the solvent is 0.1-0.2 mol:100mL;
in the step 1), the reaction temperature is 50-75 ℃, and the reaction time is 3-4 h.
Further, in the step 2), the alkaline condition is an alkaline solution, the alkaline solution contains one or more of a potassium carbonate solution, a sodium carbonate solution and a lithium carbonate solution, and the concentration of the alkaline solution is 0.65-0.8 mol/L; the molar volume ratio of the compound b to the acetic anhydride is 0.08-0.1 mol:15mL.
Further, in the step 2), the temperature of the acylation reaction is 0-60 ℃, and the time of the acylation reaction is 1-12 h.
Further, in the step 3), the molar volume ratio of the compound c, acetic anhydride and organic base is 0.07-0.09 mol: 80-90 mL: 18-22 mL; the organic base comprises one or more of triethylamine, ethylenediamine and pyridine.
Further, in the step 3), the temperature of the ring closing reaction is 60-90 ℃, and the time of the ring closing reaction is 1-6 h.
The invention provides application of a 1-acetyl-1H-indol-3-yl acetate derivative as an aldose reductase inhibitor in preparation of a medicament for treating diabetic nephropathy.
The invention has the beneficial effects that:
the existing synthesis method of the 1-acetyl-1H-indole-3-yl acetate derivative mainly comprises two routes:
route one: two-step reaction, specifically, o-chlorobenzoic acid is used as an initial raw material and reacts with glycine to prepare an intermediate compound, and the intermediate compound and acetic anhydride are subjected to acylation and cyclization reaction under the catalysis of sodium acetate to directly prepare a target product;
and a second route: three-step reaction, namely, taking anthranilic acid as a starting material, preparing an intermediate compound through alkylation and acetylation, and then preparing a target product through acylation and cyclization.
The experimental results of the comparison between the invention and the first route and the second route show that:
route one: despite the two-step reaction, the actual yield was low (< 50% overall) and the purity was low (70%);
and a second route: three-step reaction, difficult obtainment of initial raw materials, low yield (total yield less than 55%), low purity (90%) and high cost;
compared with the first route and the second route, the synthetic route of the invention has the advantages of easily obtained raw materials, high yield (total yield is more than or equal to 65%), high purity (more than or equal to 99%), low cost, simple synthetic method and more benefit for mass production.
The high-purity 1-acetyl-1H-indol-3-yl acetate derivative obtained by the invention has higher aldose reductase inhibitory activity and lower IC50 half inhibitory concentration compared with epalrestat.
Detailed Description
The invention provides a synthetic method of a 1-acetyl-1H-indole-3-yl acetate derivative, which comprises the following steps:
wherein R is H, F, cl or Br;
the method comprises the following steps:
1) Reacting halogenated benzoic acid with glycine under the action of carbonate and metal powder to obtain a compound b;
2) Performing acylation reaction on the compound b and acetic anhydride under an alkaline condition to obtain a compound c;
3) Carrying out a cyclization reaction on the compound c and acetic anhydride under the action of organic base to obtain a 1-acetyl-1H-indol-3-yl acetate derivative;
the structural general formula of the 1-acetyl-1H-indole-3-yl acetate derivative is as follows:
wherein R is H, F, cl or Br.
In the invention, the halogenated benzoic acid comprises one or more of o-fluorobenzoic acid, o-chlorobenzoic acid, o-bromobenzoic acid, 2, 6-difluorobenzoic acid, 2, 6-dichlorobenzoic acid and 2, 6-dibromobenzoic acid, and is preferably o-fluorobenzoic acid and/or o-chlorobenzoic acid.
In the present invention, the reaction of step 1) is carried out in a solvent comprising dimethylformamide and/or diisopropylethylamine, preferably dimethylformamide.
In the present invention, the carbonate comprises one or more of lithium carbonate, sodium carbonate and potassium carbonate, and preferably lithium carbonate.
In the present invention, the metal powder contains copper powder and/or iron powder, preferably copper powder.
In the present invention, the molar ratio of the halogenated benzoic acid, the glycine, the carbonate and the metal powder is 0.1:0.1 to 0.2:0.1 to 0.2:0.01 to 0.3, preferably 0.1:0.12 to 0.18:0.12 to 0.18:0.05 to 0.2, more preferably 0.1:0.15:0.15:0.1 to 0.15.
In the invention, the molar volume ratio of the glycine to the solvent is 0.1-0.2 mol:100mL, preferably 0.15mol:100mL.
In the invention, in the step 1), the reaction temperature is 50-75 ℃, and the reaction time is 3-4 h; preferably, the reaction temperature is 55-70 ℃, and the reaction time is 3.5h; more preferably, the reaction temperature is 60 to 65 ℃ and the reaction time is 3.5h.
In the present invention, in the step 2), the alkaline condition is an alkaline solution, and the alkaline solution contains one or more of a potassium carbonate solution, a sodium carbonate solution and a lithium carbonate solution, and preferably is a potassium carbonate solution.
In the present invention, in step 2), after the acylation reaction, the obtained reaction product may be acidified with hydrochloric acid to pH =2 to 3, preferably pH =3; wherein the volume ratio of the reaction product to the hydrochloric acid is 1:1.
in the present invention, the concentration of the alkali solution is 0.65 to 0.8mol/L, preferably 0.68 to 0.75mol/L, and more preferably 0.68 to 0.72mol/L.
In the invention, the molar volume ratio of the alkali, the compound b and the acetic anhydride in the alkali solution is 0.130-0.140 mol:0.08 to 0.1mol:15mL, preferably 0.132 to 0.138mol:0.09 to 0.095:15mL, more preferably 0.134 to 0.136mol:0.092 to 0.094:15mL.
In the invention, the molar volume ratio of the compound b to the acetic anhydride is 0.08-0.1 mol:15mL, preferably 0.09 to 0.095:15mL, more preferably 0.092 to 0.094:15mL.
In the invention, in the step 2), the temperature of the acylation reaction is 0-60 ℃, and the time of the acylation reaction is 1-12 h; preferably, the temperature of the acylation reaction is 0-40 ℃, and the time of the acylation reaction is 1-6 h; more preferably, the temperature of the acylation reaction is 0 to 30 ℃, and the time of the acylation reaction is 1 to 3 hours.
In the present invention, in the step 3), the molar volume ratio of the compound c, acetic anhydride and organic base is 0.07 to 0.09mol: 80-90 mL:18 to 22mL, preferably 0.075 to 0.085mol: 82-88 mL:20 to 21mL, more preferably 0.080mol:85mL:21mL.
In the invention, the organic base comprises one or more of triethylamine, ethylenediamine and pyridine, and triethylamine is preferred.
In the invention, in the step 3), the temperature of the ring closing reaction is 60-90 ℃, and the time of the ring closing reaction is 1-6 h; preferably, the temperature of the ring closing reaction is 75-85 ℃, and the time of the ring closing reaction is 2-5 ℃; further preferably, the temperature of the ring closing reaction is 80 ℃, and the time of the ring closing reaction is 3-4 h.
In the invention, in step 3), the product after the cyclization reaction is recrystallized to obtain the 1-acetyl-1H-indol-3-yl acetate derivative, and the recrystallization is carried out in an alcohol solvent, wherein the alcohol solvent contains one or more of methanol, ethanol, propanol and isopropanol, and preferably methanol and/or ethanol.
In the present invention, the 1-acetyl-1H-indol-3-yl acetate derivative is particularly preferably one of the following compounds:
TABLE 1 acetyl-1H-indol-3-yl acetate derivatives
| Compound (I) | Name (R) |
| Compound 1,AIA | 1-acetyl-1H-indol-3-yl acetate |
| Compound 2 | 1-acetyl-4-fluoroindole-3-acetic acid ester |
| Compound 3 | 1-acetyl-5-fluoroindole-3-acetic acid ester |
| Compound 4 | 1-acetyl-6-fluoroindole-3-acetic acid ester |
| Compound 5 | 1-acetyl-7-fluoroindole-3-acetic acid ester |
| Compound 6 | 1-acetyl-4-chloroindole-3-acetic acid ester |
| Compound 7 | 1-acetyl-5-chloroindole-3-acetic acid ester |
| Compound 8 | 1-acetyl-6-chloroindole-3-acetic acid ester |
| Compound 9 | 1-acetyl-7-chloroindole-3-acetic acid ester |
| Compound 10 | 1-acetyl-4-bromoindole-3-acetic acid ester |
| Compound 11 | 1-acetyl-5-bromoindole-3-acetic acid ester |
| Compound 12 | 1-acetyl-6-bromoindole-3-acetic acid ester |
| Compound 13 | 1-acetyl-7-bromoindole-3-acetic acid ester |
The invention provides application of a 1-acetyl-1H-indole-3-yl acetate derivative as an aldose reductase inhibitor in preparing a medicament for treating diabetic nephropathy.
The technical solutions provided by the present invention are described in detail below with reference to examples, but they should not be construed as limiting the scope of the present invention.
Example 1
Preparation of 1-acetyl-1H-indol-3-yl acetate (Compound 1, AIA)
1) Compound b: 15.6 g of 2-chlorobenzoic acid (0.1 moL) and 100mL of dimethylformamide were added to the reactor, and after stirring well, 11.3 g of glycine (0.15 moL) and 9.5 g of copper powder (0.15 moL) were added in this order, and then 20.7 g of potassium carbonate (0.15 moL) was added to the suspension, and the mixture was heated at 75 ℃ for 3 hours, and after completion of the reaction, the reaction was stopped. The mixture was poured into 100ml of 1.
2) Compound c: adding 18.0 g of the product of the previous step (0.092 moL) into a reactor, adding 19.1 g of potassium carbonate (0.138 moL)/180 mL of aqueous solution, stirring uniformly, dropwise adding 15mL of acetic anhydride by using a constant-pressure funnel, stirring at 50 ℃ for 1 hour after the dropwise addition is finished, adding hydrochloric acid of 1.
3) A compound d: 20.36 g of the product of the previous step (0.086 moL) was added to the reactor, and 85mL of acetic anhydride and 21mL of triethylamine were added in this order, and the temperature was slowly raised to 80 ℃ with stirring, and the reaction was controlled for 2 hours. After the reaction, the mixture was distilled under reduced pressure until no distillate was obtained, and the concentrate was poured into 400 ml of water, left overnight, filtered, and the solid was collected and dried at 60 ℃ for 3 hours. Then recrystallizing with ethanol, filtering, collecting and drying to obtain 18.3 g of product, with the yield of 91.5 percent and the purity of 99.42 percent.
Example 2
1-acetyl-4-fluoroindole-3-acetate (Compound 2)
1) Compound b: 15.8 g of 2, 6-difluorobenzoic acid (0.1 moL) and 100mL of dimethylformamide were charged into a reactor, and after stirring well, 7.5 g of glycine (0.10 moL) and 9.5 g of copper powder (0.15 moL) were added in this order, and then 20.7 g of potassium carbonate (0.15 moL) was added to the suspension and heated at 70 ℃ for 4 hours, and after completion of the reaction, the reaction was stopped. The mixture was poured into 100ml of 1.
2) Compound c: 19.2 g of the product of the previous step (0.090 moL) is added into a reactor, 18.9 g of potassium carbonate (0.137 moL)/190 mL of aqueous solution is added, after uniform stirring, 15mL of acetic anhydride is dropwise added by using a constant pressure funnel, after the dropwise addition is finished, stirring is continued for 1 hour at 20 ℃, hydrochloric acid of 1.
3) A compound d: adding 20.9 g of the product (0.082 moL) in the last step into a reactor, sequentially adding 83mL of acetic anhydride and 20mL of triethylamine, stirring, slowly heating to 80 ℃, and controlling the temperature for reaction for 2 hours. After the reaction, the mixture was distilled under reduced pressure until no distillate was obtained, and the concentrate was poured into 400 ml of water, left overnight, filtered, and the solid was collected and dried at 60 ℃ for 3 hours. Then recrystallizing with ethanol, filtering, collecting, drying to obtain 18.2 g of product, the yield is 88.3%, and the purity is 99.12%.
Example 3
1-acetyl-5-fluoroindole-3-acetate (Compound 3)
1) Compound b: 15.8 g of 2, 5-difluorobenzoic acid (0.1 moL) and 100mL of dimethylformamide were charged into a reactor, and after stirring well, 7.5 g of glycine (0.10 moL) and 9.5 g of copper powder (0.15 moL) were added in this order, and then 20.7 g of potassium carbonate (0.15 moL) was added to the suspension and heated at 70 ℃ for 3 hours, and after completion of the reaction, the reaction was stopped. The mixture was poured into 100ml of 1.
2) Compound c: 19.4 g of the product of the previous step (0.091 moL) is added into a reactor, 18.9 g of potassium carbonate (0.137 moL)/190 mL of aqueous solution is added, after uniform stirring, 15mL of acetic anhydride is added dropwise by using a constant pressure funnel, after the dropwise addition is finished, stirring is continued for 1 hour at 15 ℃, hydrochloric acid of 1.
3) A compound d: 21.2 g of the product of the previous step (0.083 moL) is added into a reactor, and 83mL of acetic anhydride and 20mL of triethylamine are sequentially added, and the temperature is slowly raised to 80 ℃ under stirring to react for 2 hours at controlled temperature. After the reaction, the mixture was distilled under reduced pressure until no distillate was obtained, and the concentrate was poured into 400 ml of water, left overnight, filtered, and the solid was collected and dried at 60 ℃ for 3 hours. Then recrystallizing with ethanol, filtering, collecting, drying to obtain 20.9 g of product, the yield is 91.5%, and the purity is 99.16%.
Example 4
1-acetyl-6-fluoroindole-3-acetate (Compound 4)
1) Compound b: 15.8 g of 2, 4-difluorobenzoic acid (0.1 moL) and 100mL of dimethylformamide were charged into a reactor, and after stirring to uniformity, 7.5 g of glycine (0.10 moL) and 9.5 g of copper powder (0.15 moL) were sequentially added, and then 20.7 g of potassium carbonate (0.15 moL) was added to the suspension and heated at 70 ℃ for 4 hours, and after completion of the reaction, the reaction was stopped. The mixture was poured into 100ml of 1.
2) Compound c: 19.1 g of the product of the last step (0.090 moL) is added into a reactor, 18.9 g of potassium carbonate (0.137 moL)/190 mL of water solution is added, after uniform stirring, 15mL of acetic anhydride is added dropwise through a constant pressure funnel, after the addition is finished, stirring is continued for 1 hour at 0 ℃, hydrochloric acid of 1.
3) A compound d: adding 20.8 g of the product (0.082 moL) in the last step into a reactor, sequentially adding 83mL of acetic anhydride and 20mL of triethylamine, stirring, slowly heating to 80 ℃, and controlling the temperature for reaction for 2 hours. After the reaction, the mixture was distilled under reduced pressure until no distillate was obtained, and the concentrate was poured into 400 ml of water, left overnight, filtered, and the solid was collected and dried at 60 ℃ for 3 hours. Then recrystallizing with ethanol, filtering, collecting and drying to obtain 18.9 g of product, wherein the yield is 92.4 percent and the purity is 99.04 percent.
Example 5
1-acetyl-7-fluoroindole-3-acetate (Compound 5)
1) Compound b: 15.8 g of 2, 3-difluorobenzoic acid (0.1 moL) and 100mL of dimethylformamide were charged into a reactor, and after stirring well, 7.5 g of glycine (0.10 moL) and 9.5 g of copper powder (0.15 moL) were added in this order, and then 20.7 g of potassium carbonate (0.15 moL) was added to the suspension and heated at 70 ℃ for 3 hours, and after completion of the reaction, the reaction was stopped. The mixture was poured into 100ml of 1.
2) Compound c: 19.9 g of the product of the previous step (0.094 moL) is added into a reactor, 18.9 g of potassium carbonate (0.137 moL)/190 mL of aqueous solution is added, after uniform stirring, 15mL of acetic anhydride is added dropwise through a constant pressure funnel, after the dropwise addition, stirring is continued for 1 hour at 30 ℃, hydrochloric acid of 1.
3) A compound d: 21.5 g of the product of the previous step (0.084 moL) is added into a reactor, 83mL of acetic anhydride and 20mL of triethylamine are sequentially added, and the temperature is slowly raised to 80 ℃ under stirring to react for 2 hours at a controlled temperature. After the reaction, the mixture was distilled under reduced pressure until no distillate was obtained, and the concentrate was poured into 400 ml of water, left overnight, filtered, and the solid was collected and dried at 60 ℃ for 3 hours. Then recrystallizing with ethanol, filtering, collecting and drying to obtain 19.5 g of product, the yield is 92.6 percent and the purity is 99.13 percent.
Example 6
1-acetyl-4-chloroindole-3-acetate (Compound 6)
1) Compound b: 19.1 g of 2, 6-dichlorobenzoic acid (0.1 moL) and 100mL of dimethylformamide were charged into a reactor, and after stirring well, 7.5 g of glycine (0.10 moL) and 6.4 g of copper powder (0.10 moL) were added in this order, and then 20.7 g of potassium carbonate (0.15 moL) was added to the suspension, and the mixture was heated at 60 ℃ for 3 hours, and after completion of the reaction, the reaction was stopped. The mixture was poured into 100ml of 1.
2) Compound c: 20.5 g of the product of the previous step (0.089 moL) was added to a reactor, 18.9 g of potassium carbonate (0.137 moL)/190 mL of aqueous solution was added, after stirring uniformly, 15mL of acetic anhydride was added dropwise from a constant pressure funnel, after the completion of the addition, stirring was continued at 45 ℃ for 1 hour, hydrochloric acid of 1.
3) A compound d: 22.0 g of the product of the previous step (0.081 moL) is added into a reactor, 83mL of acetic anhydride and 20mL of triethylamine are sequentially added, the temperature is slowly increased to 80 ℃ under stirring, and the temperature is controlled for reaction for 2 hours. After the reaction, the mixture was distilled under reduced pressure until no distillate was obtained, and the concentrate was poured into 400 ml of water, left overnight, filtered, and the solid was collected and dried at 60 ℃ for 3 hours. Then recrystallizing with ethanol, filtering, collecting and drying to obtain 19.6 g of product, the yield is 90.3%, and the purity is 99.21%.
Example 7
1-acetyl-5-chloroindole-3-acetate (Compound 7)
1) Compound b: 19.1 g of 2, 5-dichlorobenzoic acid (0.1 moL) and 100mL of dimethylformamide were charged into a reactor, and after stirring well, 7.5 g of glycine (0.10 moL) and 6.4 g of copper powder (0.10 moL) were added in this order, and then 20.7 g of potassium carbonate (0.15 moL) was added to the suspension, and the mixture was heated at 60 ℃ for 4 hours, and after completion of the reaction, the reaction was stopped. The mixture was poured into 100ml of 1.
2) Compound c: 20.4 g of the product of the previous step (0.089 moL) was added to a reactor, 18.7 g of potassium carbonate (0.135 moL)/190 mL of aqueous solution was added, after stirring uniformly, 15mL of acetic anhydride was added dropwise from a constant pressure funnel, after the addition was completed, stirring was continued at 60 ℃ for 1 hour, hydrochloric acid of 1.
3) A compound d: 21.8 g of the product of the previous step (0.081 moL) is added into a reactor, 83mL of acetic anhydride and 20mL of triethylamine are sequentially added, the temperature is slowly increased to 80 ℃ under stirring, and the temperature is controlled for reaction for 2 hours. After the reaction, the mixture was distilled under reduced pressure until no distillate was obtained, and the concentrate was poured into 400 ml of water, left overnight, filtered, and the solid was collected and dried at 60 ℃ for 3 hours. Then recrystallizing with ethanol, filtering, collecting and drying to obtain 19.3 g of product, with 89.1% of yield and 99.24% of purity.
Example 8
1-acetyl-6-chloroindole-3-acetate (Compound 8)
1) Compound b: 19.1 g of 2, 4-dichlorobenzoic acid (0.1 moL) and 100mL of dimethylformamide were charged into a reactor, and after stirring well, 7.5 g of glycine (0.10 moL) and 6.4 g of copper powder (0.10 moL) were added in this order, and then 20.7 g of potassium carbonate (0.15 moL) was added to the suspension, and the mixture was heated at 60 ℃ for 3 hours, and after completion of the reaction, the reaction was stopped. The mixture was poured into 100ml of 1.
2) Compound c: 20.2 g of the product of the previous step (0.088 moL) was added to a reactor, 18.2 g of potassium carbonate (0.132 moL)/190 mL of aqueous solution was added, after stirring uniformly, 15mL of acetic anhydride was added dropwise from a constant pressure funnel, after the addition was completed, stirring was continued at 35 ℃ for 1 hour, hydrochloric acid of 1.
3) A compound d: 21.3 g of the product of the previous step (0.078 moL) is added into a reactor, 83mL of acetic anhydride and 20mL of triethylamine are sequentially added, the temperature is slowly increased to 80 ℃ under stirring, and the temperature is controlled for reaction for 2 hours. After the reaction, the mixture was distilled under reduced pressure until no distillate was obtained, and the concentrate was poured into 400 ml of water, left overnight, filtered, and the solid was collected and dried at 60 ℃ for 3 hours. Then recrystallizing with ethanol, filtering, collecting and drying to obtain 19.1 g of product, with the yield of 91.5 percent and the purity of 99.35 percent.
Example 9
1-acetyl-7-chloroindole-3-acetate (Compound 9)
1) Compound b: 19.1 g of 2, 3-dichlorobenzoic acid (0.1 moL) and 100mL of dimethylformamide were charged into a reactor, and after stirring well, 7.5 g of glycine (0.10 moL) and 6.4 g of copper powder (0.10 moL) were added in this order, and then 20.7 g of potassium carbonate (0.15 moL) was added to the suspension, and the mixture was heated at 60 ℃ for 4 hours, and after completion of the reaction, the reaction was stopped. The mixture was poured into 100ml of 1.
2) Compound c: adding 20.3 g of the product of the previous step (0.088 moL) into a reactor, adding 18.9 g of potassium carbonate (0.137 moL)/190 mL of water solution, stirring uniformly, dropwise adding 15mL of acetic anhydride by using a constant pressure funnel, continuing stirring at 30 ℃ for 1 hour after the dropwise adding is finished, adding hydrochloric acid of 1.
3) A compound d: 22.0 g of the product of the previous step (0.081 moL) is added into a reactor, 83mL of acetic anhydride and 20mL of triethylamine are sequentially added, the temperature is slowly increased to 80 ℃ under stirring, and the temperature is controlled for reaction for 2 hours. After the reaction, the mixture was distilled under reduced pressure until no distillate was obtained, and the concentrate was poured into 400 ml of water, left overnight, filtered, and the solid was collected and dried at 60 ℃ for 3 hours. Then recrystallizing with ethanol, filtering, collecting and drying to obtain 19.5 g of product, wherein the yield is 89.9 percent and the purity is 99.15 percent.
Example 10
1-acetyl-4-bromoindole-3-acetate (Compound 10)
1) Compound b: 28.0 g of 2, 6-dibromobenzoic acid (0.10 moL) and 100mL of dimethylformamide were added to the reactor, and after stirring well, 7.5 g of glycine (0.10 moL) and 3.2 g of copper powder (0.05 moL) were added in this order, and then 20.7 g of potassium carbonate (0.15 moL) was added to the suspension, and the mixture was heated at 50 ℃ for 3.5 hours, and after completion of the reaction, the reaction was stopped. The mixture was poured into 100ml of 1.
2) Compound c: adding 24.0 g of the product of the previous step (0.088 moL) into a reactor, adding 19.1 g of potassium carbonate (0.138 moL)/190 mL of aqueous solution, stirring uniformly, dropwise adding 15mL of acetic anhydride by using a constant-pressure funnel, continuing stirring at 40 ℃ for 1 hour after the dropwise adding is finished, adding hydrochloric acid of 1.
3) A compound d: adding 25.1 g of the product (0.079 moL) in the last step into a reactor, sequentially adding 80mL of acetic anhydride and 20mL of triethylamine, stirring, slowly heating to 80 ℃, and controlling the temperature to react for 2 hours. After the reaction, the mixture was distilled under reduced pressure until no distillate was obtained, and the concentrate was poured into 400 ml of water, left overnight, filtered, and the solid was collected and dried at 60 ℃ for 3 hours. Then recrystallizing with ethanol, filtering, collecting and drying to obtain 22.6 g of product, with the yield of 91.5 percent and the purity of 99.07 percent.
Example 11
1-acetyl-5-bromoindole-3-acetate (Compound 11)
1) Compound b: 28.0 g of 2, 5-dibromobenzoic acid (0.10 moL) and 100mL of dimethylformamide were added to the reactor, and after stirring well, 7.5 g of glycine (0.10 moL) and 3.2 g of copper powder (0.05 moL) were added in this order, and then 20.7 g of potassium carbonate (0.15 moL) was added to the suspension, and the mixture was heated at 50 ℃ for 4 hours, and after completion of the reaction, the reaction was stopped. The mixture was poured into 100ml of 1.
2) Compound c: 24.5 g of the product of the previous step (0.089 moL) was added to a reactor, 19.1 g of potassium carbonate (0.138 moL)/190 mL of aqueous solution was added, after stirring uniformly, 15mL of acetic anhydride was added dropwise from a constant pressure funnel, after the addition was completed, stirring was continued at 20 ℃ for 1 hour, hydrochloric acid of 1.
3) A compound d: adding 25.4 g of the product (0.080 moL) of the last step into a reactor, sequentially adding 80mL of acetic anhydride and 20mL of triethylamine, stirring, slowly heating to 80 ℃, and controlling the temperature for reaction for 2 hours. After the reaction, the mixture was distilled under reduced pressure until no distillate was obtained, and the concentrate was poured into 400 ml of water, left overnight, filtered, and the solid was collected and dried at 60 ℃ for 3 hours. Then recrystallizing with ethanol, filtering, collecting and drying to obtain 23.1 g of product, the yield is 92.6 percent and the purity is 99.11 percent.
Example 12
1-acetyl-6-bromoindole-3-acetate (Compound 12)
1) Compound b: 28.0 g of 2, 4-dibromobenzoic acid (0.10 moL) and 100mL of dimethylformamide were added to the reactor, and after stirring well, 7.5 g of glycine (0.10 moL) and 3.2 g of copper powder (0.05 moL) were added in this order, and then 20.7 g of potassium carbonate (0.15 moL) was added to the suspension, and the mixture was heated at 50 ℃ for 3 hours, and after completion of the reaction, the reaction was stopped. The mixture was poured into 100ml of 1.
2) Compound c: adding 24.2 g of the product of the previous step (0.088 moL) into a reactor, adding 19.1 g of potassium carbonate (0.138 moL)/190 mL of aqueous solution, stirring uniformly, dropwise adding 15mL of acetic anhydride by using a constant-pressure funnel, continuing stirring at 45 ℃ for 1 hour after the dropwise adding is finished, adding hydrochloric acid of 1.
3) A compound d: adding 25.2 g of the product (0.080 moL) of the last step into a reactor, sequentially adding 80mL of acetic anhydride and 20mL of triethylamine, stirring, slowly heating to 80 ℃, and controlling the temperature for reaction for 2 hours. After the reaction, the mixture was distilled under reduced pressure until no distillate was obtained, and the concentrate was poured into 400 ml of water, left overnight, filtered, and the solid was collected and dried at 60 ℃ for 3 hours. Then recrystallizing with ethanol, filtering, collecting and drying to obtain 23.2 g of product, with 93.1% of yield and 99.22% of purity.
Example 13
1-acetyl-7-bromoindole-3-acetate (Compound 13)
1) Compound b: 28.0 g of 2, 3-dibromobenzoic acid (0.10 moL) and 100mL of dimethylformamide were added to the reactor, and after stirring to be uniform, 7.5 g of glycine (0.10 moL) and 3.2 g of copper powder (0.05 moL) were added in this order, and then 20.7 g of potassium carbonate (0.15 moL) was added to the suspension, and the mixture was heated at 50 ℃ for 4 hours, and after completion of the reaction, the reaction was stopped. The mixture was poured into 100ml of 1.
2) Compound c: adding 24.0 g of the product of the previous step (0.088 moL) into a reactor, adding 19.1 g of potassium carbonate (0.138 moL)/190 mL of aqueous solution, stirring uniformly, dropwise adding 15mL of acetic anhydride by using a constant-pressure funnel, continuing stirring at 55 ℃ for 1 hour after the dropwise adding is finished, adding hydrochloric acid of 1.
3) A compound d: 24.8 g of the product of the previous step (0.078 moL) is added into a reactor, 80mL of acetic anhydride and 20mL of triethylamine are sequentially added, the temperature is slowly increased to 80 ℃ under stirring, and the temperature is controlled for reaction for 2 hours. After the reaction, the mixture was distilled under reduced pressure until no distillate was obtained, and the concentrate was poured into 400 ml of water, left overnight, filtered, and the solid was collected and dried at 60 ℃ for 3 hours. Then recrystallizing with ethanol, filtering, collecting and drying to obtain 22.6 g of product, wherein the yield is 92.8 percent and the purity is 99.07 percent.
Experimental example 1
1-acetyl-1H-indol-3-yl acetate derivatives aldose reductase inhibitors IC50 assay
1) ARIs activity assay system: the enzymatic reaction system consists of: the total volume was 1mL, wherein the amount of 5mM DL-glyceraldehyde was 100. Mu.L, 0.15mM NADPH was 100. Mu.L, the amount of AR was 100. Mu.L, 0.6mM lithium sulfate was 100. Mu.L, and the balance was made up with 0.1M phosphate buffer (pH 6.2), the reaction time was 1min, the reaction temperature was 37 ℃, as shown in Table 2.
TABLE 2 aldose reductase inhibitor screening model
Determination of the activity of ARIs: respectively adding target compounds 1-13 into PB buffer solution for dissolving, diluting to form concentration gradients, and adding a proper amount of DMSO for assisting dissolution, wherein DMSO is not more than 5% in a test system. The positive control epalrestat was used as a positive control to measure the inhibition rate of AR at each concentration of compounds 1 to 13, and the inhibition percentage was plotted against the inhibitor concentration to obtain the IC50 of epalrestat and compounds 1 to 13 from the inhibition curve, as shown in table 3 below.
TABLE 3 aldose reductase inhibitors of 1-acetyl-1H-indol-3-yl acetate derivatives IC50
Experimental example 2
Effect of AIA on apoptosis of mesangial cells (HBZY-1)
1) Establishing a high-sugar induced apoptosis model: the method comprises the following steps: HBZY-1 cells were cultured at 10 deg.C 4 Inoculating the cells/well into a 96-well plate, culturing for 12h until the cells are completely attached to the wall, discarding the culture medium, respectively adding DMEM culture media containing different glucose concentrations (22 mM, 33mM and 44 mM) and culturing for 24h, 36h, 72h and 96h, and detecting the apoptosis condition by using an MTT method to determine the optimal conditions for inducing apoptosis by high glucose. As a result: experiments prove that compared with the control group, the sugar concentration is 33mM, the inhibitory effect on HBZY-1 cells is most obvious when the cells are cultured for 72 hours, and the cell damage is not changed more obviously when the culture time is prolonged.
Effect of AIA on proliferation of mesangial cells (HBZY-1): the method comprises the following steps: HBZY-1 cells were cultured at 10 deg.C 4 Density of individual/well inoculated in 96-well plates, 37 ℃ 5% CO 2 After culturing for 12h, completely attaching the cells to the wall, removing the culture medium, treating the cells for 1h with different concentrations of AIA drugs, setting 3-5 multiple holes, setting zero-setting holes (culture medium, MTT and dimethyl sulfoxide) and control holes (cells, drug dissolution medium with the same concentration, culture solution, MTT and dimethyl sulfoxide); 33mmol/L glucose was added and 4h before the end of the cell culture 15. Mu.l MTT (5 mg `) were added per wellmL, i.e., 0.5% MTT), after the culture was completed, the medium was aspirated, 150. Mu.l of DMSO was added to each well, the well was shaken at low speed for 10min at 37 ℃ on a shaker to dissolve the crystals sufficiently, and the absorbance of each well was measured at OD 490nm in an enzyme linked immunosorbent assay. Experimental grouping conditions: (1) blank control group (NS, DMEM low-sugar medium); (2) high glucose induction group (HG, DMEM low sugar medium +33mM glucose); (3) AIA administration group (low dose AL-0.3. Mu.M, medium dose AM-0.6. Mu.M, high dose AH-0.9. Mu.M); (4) EPS-10. Mu.M positive control group; inducing above groups for more than 24 hr, digesting with 0.05% trypsin to obtain single cell suspension, and adjusting cell concentration to 10 6 Each group was cultured at a sugar concentration of 33mmol/L for 72 hours, and the results were measured.
The experimental results are as follows: compared with NS group, OD value of each experimental group is reduced, HG, AL, AM and EPS group P is less than 0.001, AH group P is less than 0.05. Compared with the HG group, the OD values of the AM group and the EPS group are obviously increased by P <0.05, and the OD value of the AH group is increased most obviously by P <0.01.
Application example 1
Preparation of AIA oral capsule
The oral capsule comprises the following raw materials in proportion:
preparation filling: taking 300 g of AIA which passes through a 100-mesh sieve, uniformly mixing with 30 g of starch, adding a proper amount of 50% ethanol, stirring, sieving with a 18-mesh sieve, preparing into granules with proper elasticity, drying at 60-70 ℃, sieving dry granules with a 16-mesh sieve, adding 3.0 g of magnesium stearate, uniformly mixing, preparing into 1000 granules, measuring the content, and filling.
Application example 2
Preparation of AIA tablets
The raw material ratio of the oral tablet is as follows:
and (3) filling the preparation: mixing 200 g of AIA passing through a 100-mesh sieve with 30 g of starch uniformly, adding a proper amount of 50% ethanol, stirring, sieving with a 18-mesh sieve, preparing into granules with proper elasticity, drying at 60-70 ℃, sieving the dried granules with a 16-mesh sieve, adding 3.0 g of magnesium stearate, mixing uniformly, preparing into 1000 granules, measuring the moisture and content, tabletting, checking to be qualified and packaging.
From the above examples, the present invention provides a synthesis method and application of 1-acetyl-1H-indol-3-yl acetate derivatives. The invention takes halogenated benzoic acid as raw material, reacts with glycine under the alkaline condition through metal catalysis, then acidylates with acetic anhydride under the alkaline condition, finally prepares a crude product with the acetic anhydride through organic base catalysis ring closure, and the crude product is recrystallized in an alcohol solvent to prepare the 1-acetyl-1H-indol-3-yl acetate derivative; the derivatives are useful as aldose reductase inhibitors, and have utility in the preparation of candidate drug molecules for the treatment of diabetic nephropathy. The synthesis method has the advantages of simple operation, easily obtained raw materials, high yield, high purity and low cost, and is beneficial to mass production.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and amendments can be made without departing from the principle of the present invention, and these modifications and amendments should also be considered as the protection scope of the present invention.
Claims (10)
1. A synthetic method of 1-acetyl-1H-indol-3-yl acetate derivatives is characterized in that the synthetic route is as follows:
wherein R is H, F, cl or Br;
the method comprises the following steps:
1) Reacting halogenated benzoic acid with glycine under the action of carbonate and metal powder to obtain a compound b;
2) Performing acylation reaction on the compound b and acetic anhydride under an alkaline condition to obtain a compound c;
3) Carrying out a cyclization reaction on the compound c and acetic anhydride under the action of organic base to obtain a 1-acetyl-1H-indol-3-yl acetate derivative;
the structural general formula of the 1-acetyl-1H-indole-3-yl acetate derivative is as follows:
wherein R is H, F, cl or Br.
2. The synthesis method according to claim 1, wherein the halogenated benzoic acid comprises one or more of o-fluorobenzoic acid, o-chlorobenzoic acid, o-bromobenzoic acid, 2, 6-difluorobenzoic acid, 2, 6-dichlorobenzoic acid and 2, 6-dibromobenzoic acid.
3. The synthesis process according to claim 2, characterized in that the reaction of step 1) is carried out in a solvent comprising dimethylformamide and/or diisopropylethylamine.
4. The synthesis method according to claim 3, wherein the carbonate comprises one or more of lithium carbonate, sodium carbonate and potassium carbonate; the metal powder comprises copper powder and/or iron powder; the molar ratio of the halogenated benzoic acid to the glycine to the carbonate to the metal powder is 0.1:0.1 to 0.2:0.1 to 0.2:0.01 to 0.3.
5. The synthesis method according to claim 3 or 4, wherein the molar volume ratio of glycine to solvent is 0.1-0.2 mol:100mL; in the step 1), the reaction temperature is 50-75 ℃, and the reaction time is 3-4 h.
6. The synthesis method according to claim 5, wherein in the step 2), the alkaline condition is an alkaline solution, the alkaline solution comprises one or more of a potassium carbonate solution, a sodium carbonate solution and a lithium carbonate solution, and the concentration of the alkaline solution is 0.65-0.8 mol/L; the molar volume ratio of the compound b to the acetic anhydride is 0.08-0.1 mol:15mL.
7. The synthesis method according to claim 1 or 2 or 4 or 6, wherein in the step 2), the temperature of the acylation reaction is 0-60 ℃, and the time of the acylation reaction is 1-12 h.
8. The synthesis method according to claim 7, wherein in the step 3), the molar volume ratio of the compound c, acetic anhydride and organic base is 0.07-0.09 mol: 80-90 mL: 18-22 mL; the organic base comprises one or more of triethylamine, ethylenediamine and pyridine.
9. The synthesis method as claimed in claim 8, wherein in the step 3), the temperature of the ring closing reaction is 60-90 ℃, and the time of the ring closing reaction is 1-6 h.
10. Use of a 1-acetyl-1H-indol-3-yl acetate derivative obtained by a synthesis according to any one of claims 1 to 9 as an aldose reductase inhibitor in the manufacture of a medicament for the treatment of diabetic nephropathy.
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