CN106986809B - Synthesis method of 5-bromo-6-chloro-3-indoxyl - Google Patents
Synthesis method of 5-bromo-6-chloro-3-indoxyl Download PDFInfo
- Publication number
- CN106986809B CN106986809B CN201611095606.3A CN201611095606A CN106986809B CN 106986809 B CN106986809 B CN 106986809B CN 201611095606 A CN201611095606 A CN 201611095606A CN 106986809 B CN106986809 B CN 106986809B
- Authority
- CN
- China
- Prior art keywords
- chloro
- bromo
- aminobenzoic acid
- reaction
- ester
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000001308 synthesis method Methods 0.000 title description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- 150000002148 esters Chemical class 0.000 claims abstract description 18
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims abstract description 16
- TUDNMLBIHIWVJM-UHFFFAOYSA-N 2-amino-5-bromo-4-chlorobenzoic acid Chemical compound NC1=CC(Cl)=C(Br)C=C1C(O)=O TUDNMLBIHIWVJM-UHFFFAOYSA-N 0.000 claims abstract description 15
- FDRCDNZGSXJAFP-UHFFFAOYSA-M sodium chloroacetate Chemical compound [Na+].[O-]C(=O)CCl FDRCDNZGSXJAFP-UHFFFAOYSA-M 0.000 claims abstract description 7
- JYYLQSCZISREGY-UHFFFAOYSA-N 2-amino-4-chlorobenzoic acid Chemical compound NC1=CC(Cl)=CC=C1C(O)=O JYYLQSCZISREGY-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims abstract description 6
- REEZZSHJLXOIHL-UHFFFAOYSA-N octanoyl chloride Chemical compound CCCCCCCC(Cl)=O REEZZSHJLXOIHL-UHFFFAOYSA-N 0.000 claims abstract description 5
- ZGUNAGUHMKGQNY-ZETCQYMHSA-N L-alpha-phenylglycine zwitterion Chemical compound OC(=O)[C@@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-ZETCQYMHSA-N 0.000 claims abstract 6
- 238000010189 synthetic method Methods 0.000 claims abstract 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 238000005893 bromination reaction Methods 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- 238000005886 esterification reaction Methods 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- 238000002390 rotary evaporation Methods 0.000 claims description 3
- 239000000725 suspension Substances 0.000 claims description 3
- 230000032050 esterification Effects 0.000 claims description 2
- 239000000758 substrate Substances 0.000 claims description 2
- 238000002386 leaching Methods 0.000 claims 1
- 239000007858 starting material Substances 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 13
- 230000015572 biosynthetic process Effects 0.000 abstract description 12
- 238000006114 decarboxylation reaction Methods 0.000 abstract description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 abstract description 6
- 238000000034 method Methods 0.000 abstract description 6
- 238000007363 ring formation reaction Methods 0.000 abstract description 6
- 229910052794 bromium Inorganic materials 0.000 abstract description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 abstract 1
- 125000001246 bromo group Chemical group Br* 0.000 abstract 1
- 229910052738 indium Inorganic materials 0.000 abstract 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 abstract 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 abstract 1
- 238000006467 substitution reaction Methods 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- -1 5-bromo-6-chloro-3-indolyloctyl ester Chemical class 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-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
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 230000031709 bromination Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 2
- 239000003593 chromogenic compound Substances 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- KMAKOBLIOCQGJP-UHFFFAOYSA-N indole-3-carboxylic acid Chemical class C1=CC=C2C(C(=O)O)=CNC2=C1 KMAKOBLIOCQGJP-UHFFFAOYSA-N 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical group O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- UVGYSEIWAOOIJR-UHFFFAOYSA-N 4-chloro-2-fluorobenzaldehyde Chemical compound FC1=CC(Cl)=CC=C1C=O UVGYSEIWAOOIJR-UHFFFAOYSA-N 0.000 description 1
- HWUOPUMSIRQTGW-UHFFFAOYSA-N 5-bromo-2,4-dichlorobenzoic acid Chemical compound OC(=O)C1=CC(Br)=C(Cl)C=C1Cl HWUOPUMSIRQTGW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 238000010751 Ullmann type reaction Methods 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- SWLVFNYSXGMGBS-UHFFFAOYSA-N ammonium bromide Chemical compound [NH4+].[Br-] SWLVFNYSXGMGBS-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000003344 environmental pollutant Substances 0.000 description 1
- VOXANKRFRUBRGI-UHFFFAOYSA-N ethylamino acetate hydrochloride Chemical compound Cl.CCNOC(C)=O VOXANKRFRUBRGI-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- JYQQWQJCEUMXQZ-UHFFFAOYSA-N methyl cyanate Chemical compound COC#N JYQQWQJCEUMXQZ-UHFFFAOYSA-N 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 231100000719 pollutant Toxicity 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/36—Oxygen atoms in position 3, e.g. adrenochrome
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
本发明公开了一种5‑溴‑6‑氯‑3‑吲哚辛酯的合成方法，其特征在于，将4‑氯‑2‑氨基苯甲酸与N‑溴代丁二酰亚胺经过溴代反应得到5‑溴‑4‑氯‑2‑氨基苯甲酸，5‑溴‑4‑氯‑2‑氨基苯甲酸与氯乙酸钠经过亲核取代反应得到N‑(4‑溴‑5‑氯‑2‑羧基)苯基甘氨酸，N‑(4‑溴‑5‑氯‑2‑羧基)苯基甘氨酸再经环化脱羧反应得到1‑乙酰基‑5‑溴‑6‑氯‑3‑吲哚乙酯，1‑乙酰基‑5‑溴‑6‑氯‑3‑吲哚乙酯与辛酰氯选择性酯化反应得到5‑溴‑6‑氯‑3‑吲哚辛酯。本发明的5‑溴‑6‑氯‑3‑吲哚辛酯的合成方法，其高效、安全环保、反应总产率相对较高，因此可以用于5‑溴‑6‑氯‑3‑吲哚辛酯的大规模合成。
The invention discloses a method for synthesizing 5-bromo-6-chloro-3-indoloctyl ester, which is characterized in that 4-chloro-2-aminobenzoic acid and N-bromosuccinimide are subjected to bromine Substitution reaction to obtain 5-bromo-4-chloro-2-aminobenzoic acid, 5-bromo-4-chloro-2-aminobenzoic acid and sodium chloroacetate through nucleophilic substitution reaction to obtain N-(4-bromo-5-chloro- -2-carboxy) phenylglycine, N-(4-bromo-5-chloro-2-carboxy) phenylglycine through cyclization decarboxylation to obtain 1-acetyl-5-bromo-6-chloro-3-indium Indole ethyl ester, 1-acetyl-5-bromo-6-chloro-3-indole ethyl ester and octanoyl chloride are selectively esterified to obtain 5-bromo-6-chloro-3-indole octyl ester. The synthetic method of 5-bromo-6-chloro-3-indole octyl ester of the present invention is efficient, safe and environmentally friendly, and the total reaction yield is relatively high, so it can be used for 5-bromo-6-chloro-3-indole Large-scale synthesis of indoctyl ester.
Description
The technical field is as follows:
the invention belongs to the technical field of organic synthesis and biological analysis and detection, and particularly relates to a synthesis method of 5-bromo-6-chloro-3-indoxyl.
Background art:
holt et al (Proc. R. Soc. B,1958,148,481-494) have reported that a series of differently substituted 1-acetyl-3-indoleethyl esters were synthesized via different routes starting from three compounds, halogenated aniline, anthranilic acid, N- (2-carboxy) phenylglycine substituent, followed by the further synthesis of differently substituted chromogenic substrates of the acetate class. Wherein, the synthesis of the 5-bromo-6-chloro-3-indoleethyl ester involves: n- (5-chloro-2-carboxyl) phenylglycine is subjected to aromatic ring bromination reaction under the condition of liquid bromine/acetic acid (the yield is 78%), the obtained N- (4-bromo-5-chloro-2-carboxyl) phenylglycine is subjected to cyclization decarboxylation reaction under the condition of acetic anhydride/sodium acetate/heating reflux (the yield is 42%), the obtained 1-acetyl-5-bromo-6-chloro-3-indoleethyl ester is subjected to hydrolysis to remove all acetyl groups, and then is subjected to esterification reaction with acetic anhydride selectively (the yield is 42%); the total yield of the three steps of reactions is 14 percent, and is shown as a formula 1.
Another method of synthesis of 1-acetyl-5-bromo-6-chloro-3-indoleethyl ester has been reported by Rodri i guez-Dom i anguez et al (J.heterocyclic. chem.,2007,44, 273-),275, the method is characterized in that 2, 4-dichlorobenzoic acid is used as an initial raw material, bromination reaction is firstly carried out under liquid bromine/chlorosulfonic acid/elemental sulfur/heating conditions (yield is 95%), the obtained 5-bromo-2, 4-dichlorobenzoic acid is subjected to Ullmann condensation reaction under glycine/potassium carbonate/copper powder/N, N-Dimethylformamide (DMF)/heating reflux (yield is 71%), and the obtained N- (4-bromo-5-chloro-2-carboxyl) phenylglycine is subjected to cyclization decarboxylation reaction under acetic anhydride/sodium acetate/heating reflux conditions (yield is 64%) to obtain the final product; the total yield of the three steps of reactions is 43 percent, as shown in formula 2.
A new synthesis of 1-acetyl-5-bromo-6-chloro-3-indoleethyl ester has been reported recently by Gandy et al (org. Biomol. chem.,2015,13, 905-908). The method comprises the steps of taking 4-chloro-2-fluorobenzaldehyde as an initiator, sequentially carrying out nucleophilic addition with hydroxylamine hydrochloride, then carrying out dehydration reaction (yield is 84%), carrying out condensation reaction with ethyl aminoacetate hydrochloride (yield is 72%), carrying out aromatic ring bromination reaction with ammonium bromide and hydrogen peroxide (yield is 81%), carrying out hydrolysis reaction (yield is 95%) and finally carrying out ring-closing decarboxylation reaction (yield is 88%; note: no recrystallization) to obtain a target product; the total yield of the five reactions is 41%, as shown in formula 3.
Agban et al (Eur.J.Med.chem.,1990,25, 697-via 699) reported the synthesis of a variety of 3-indole carboxylic acid esters, but only involved a one-step reaction from a variety of 1-acetyl-3-indole ethyl esters (but no 1-acetyl-5-bromo-6-chloro-3-indole ethyl ester) to a variety of 3-indole carboxylic acid esters, and neither gave a yield nor synthesized 5-bromo-6-chloro-3-indolyltctyl ester.
The above synthetic studies have the following problems: the synthetic route and the specific preparation process of the 5-bromo-6-chloro-3-indoxyl ester are not reported; for the synthesis of an intermediate, during bromination reaction, high-toxicity liquid bromine is used as a bromination reagent, and solvents such as acetic acid, chlorosulfonic acid and the like are difficult to recover, so that more pollutants are easily generated; the overall yield of other step reactions or intermediate reaction routes is low, and the like.
The invention content is as follows:
the invention aims to provide a synthesis method of 5-bromo-6-chloro-3-indoxyl with high efficiency, safety, environmental protection and relatively high total reaction yield. 5-bromo-6-chloro-3-indoxyl is currently commonly used as a chromogenic substrate (or chromogenic probe) for the detection of Salmonella containing specific octanoate esterase in the field of microbial detection.
The synthesis method of 5-bromo-6-chloro-3-indolyloctyl ester is characterized by comprising the following steps:
carrying out bromination reaction on 4-chloro-2-aminobenzoic acid and N-bromosuccinimide to obtain 5-bromo-4-chloro-2-aminobenzoic acid, carrying out nucleophilic substitution reaction on 5-bromo-4-chloro-2-aminobenzoic acid and sodium chloroacetate to obtain N- (4-bromo-5-chloro-2-carboxyl) phenylglycine, carrying out cyclization decarboxylation reaction on the N- (4-bromo-5-chloro-2-carboxyl) phenylglycine to obtain 1-acetyl-5-bromo-6-chloro-3-indoleethyl ester, and carrying out selective esterification reaction on 1-acetyl-5-bromo-6-chloro-3-indoleethyl ester and octanoyl chloride to obtain 5-bromo-6-chloro-3-indoleoctylene And (3) an ester.
The specific synthetic route is shown as the following formula:
bromination reaction, nucleophilic substitution reaction, cyclization decarboxylation reaction and selective esterification reaction with octanoyl chloride, wherein the reaction yield of each step is 98%, 84%, 68% and 47% in sequence, and the total yield of the four steps is 26%.
Wherein, solvent acetonitrile used in bromination reaction is easy to recycle and can be recycled due to low boiling point, NBS used is solid bromine reagent, and corresponding by-product is succinimide; compared with the bromination reaction using HBr as one of the liquid bromine and reaction byproducts in the background art, the bromination method of the invention is obviously safer and more environment-friendly, and the yield is also very high.
For the nucleophilic substitution of sodium chloroacetate in the one-step reaction, KI is added as a catalyst, so that the reaction rate can be accelerated. For the two reactions of the cyclization decarboxylation and the final selective esterification, the invention also makes corresponding changes which are beneficial to improving the reaction yield, such as proper adjustment of the charge ratio, control of the reaction temperature and time, change of the post-reaction treatment and the like.
The synthesis method of 5-bromo-6-chloro-3-indoxyl ester has the advantages of high efficiency, safety, environmental protection and relatively high total reaction yield, so that the method can be used for large-scale synthesis of 5-bromo-6-chloro-3-indoxyl ester.
Description of the drawings:
FIG. 1 is H spectrum data of 1-acetyl-5-bromo-6-chloro-3-indoleethyl ester;
FIG. 2 is C spectrum data of 1-acetyl-5-bromo-6-chloro-3-indoleethyl ester;
FIG. 3 is H spectrum data of 5-bromo-6-chloro-3-indolyloctyl ester;
FIG. 4 is C spectrum data of 5-bromo-6-chloro-3-indoxyl ester.
The specific implementation mode is as follows:
the following examples are further illustrative of the present invention and are not intended to be limiting thereof.
Example 1:
the synthetic route of this example is shown below:
(1) synthesis of 5-bromo-4-chloro-2-aminobenzoic acid (II)
4-chloro-2-aminobenzoic acid (I; 20.00g, 116.6mmol) is added into a 500mL single-neck round-bottom flask, then acetonitrile (300mL) is added, the mixture is rapidly stirred to form a beige suspension, N-bromosuccinimide (NBS; 20.75g, 116.6mmol) is slowly added into the suspension in small amount for multiple times at room temperature, after the addition is finished, the reaction is continuously stirred for 1h, then the solvent is removed by rotary evaporation in a water bath at 45 ℃, water is added, the mixture is stirred, filtered, washed and dried in vacuum at 60 ℃ to obtain the required target 5-bromo-4-chloro-2-aminobenzoic acid (II, 28.62g, the yield is 98%).
Nuclear magnetic data for 5-bromo-4-chloro-2-aminobenzoic acid:1H-NMR(300MHz,DMSO-d6):δ＝7.90(s,1H,—H-6)；7. 02(s,1H,H-3).13C-NMR(75MHz,DMSO-d6):δ＝167.69(CO2H)；151.23(C-2)；137.79(C-4)；13 5.37(C-6)；117.13(C-3)；110.34(C-1)；103.98(C-5).
(2) synthesis of N- (4-bromo-5-chloro-2-carboxy) phenylglycine (III)
To a 150mL two-necked round bottom flask was added 5-bromo-4-chloro-2-aminobenzoic acid (II; 5.00g, 19.96mmol), NaOH (0.83g, 20.74mmol) and water (40mL), stirred until the solid dissolved, and KI (0.34g, 2.05mmol), sodium chloroacetate (4.83g, 41.47mmol) and Na were added sequentially2CO3Adjusting the pH value of the (2mol/L) solution to 7-8, heating and reacting under reflux, and continuously adding Na2CO3And (3) adjusting the pH value of the solution (2mol/L) to 7-8, stopping heating and stirring when the pH value of the reaction solution is not changed within 45min, cooling, adding 40mL of water for dilution, acidifying with concentrated hydrochloric acid until the pH value is 4, performing suction filtration, washing with cold water, performing vacuum drying at 60 ℃ after suction drying, and performing extraction with acetonitrile to remove a small amount of residual unreacted substrate raw material to obtain the required target product N- (4-bromo-5-chloro-2-carboxyl) phenylglycine (III; 5.20g, yield 84%).
Nuclear magnetic data for N- (4-bromo-5-chloro-2-carboxy) phenylglycine:1H-NMR(300MHz,DMSO-d6):δ＝13.07(s,2H,- CO2H)；8.18(s,1H,-NH-)；7.98(s,1H,H-6)；6.87(s,1H,H-3)；4.02(t,2H,-CH2-)ppm.13C-NMR(75 MHz,DMSO-d6):δ＝171.24(CO2H)；167.88(CO2H)；149.68(C-2)；138.73(C-4)；135.62(C-6)； 113.38(C-3)；111.19(C-1)；104.60(C-5)；44.11(CH2)ppm.
(3) synthesis of 1-acetyl-5-bromo-6-chloro-3-indoleethyl ester (IV)
Weighing N- (4-bromo-5-chloro-2-carboxy) phenylglycine (III; 5.000g, 16.21mmol) and anhydrous sodium acetate (5.318g, 64.83mmol, 4.0equiv.) and placing the mixture in a 150mL two-neck round-bottom flask, adding acetic anhydride (75mL), placing the mixture in an oil bath preheated to about 150 ℃, stirring and reacting at 135-140 ℃ until no carbon dioxide is generated (about 25min), taking out, cooling, adding a large amount of ice-water mixture, stirring in an ice-water bath or standing until an oily substance disappears, performing suction filtration, washing with saturated sodium bicarbonate to neutrality, fully washing with water, performing suction drying, washing with a small amount of cold methanol, performing ethanol-water recrystallization, fully performing vacuum drying to obtain the required target 1-acetyl-5-bromo-6-chloro-3-indole ethyl ester (IV; 3.644g, yield 68%).
Nuclear magnetic data for 1-acetyl-5-bromo-6-chloro-3-indoleethyl ester:1H-NMR(300MHz,CDCl3):δ＝8.65(s,1H,H-2)； 7.80(s,1H,H-4)；7.75(s,1H,H-7)；2.61(s,3H,-OCOCH3)；2.40(s,3H,＝NCOCH3)ppm.13C-NMR(75MHz,CDCl3):δ＝168.47(-OCO-)；167.53(＝NCO-)；133.14(C-7a)；131.99(C-3a)； 131.75(C-6)；123.43(C-2)；121.93(C-4)；118.37(C-3)；117.45(C-5)；114.63(C-7)；23.68,20.98 (2×CH3)ppm.HRMS:calcd.for C12H9BrClNNaO3351.9347; found 351.9349 (FIGS. 1 and 2)
(4) Synthesis of 5-bromo-6-chloro-3-indolyloctyl ester (V)
Weighing 1-acetyl-5-bromo-6-chloro-3-indole ethyl ester (IV; 0.992g, 3.00mmol), placing in a 50mL round bottom flask, adding NaOH solution (2mol/L, 16.5mL), removing oxygen sufficiently, and adding N2Heating and refluxing for reaction under protection until the solid is completely dissolved to obtain uniform black-brown opaque liquid, cooling, transferring to ice water bath for cooling, adding octanoyl chloride (2.9mL) under rapid stirring, reacting for 0.5h, and stopping introducing N2The reaction was terminated. The upper aqueous solution was decanted off and 1mol/L Na was added2CO3Stirring the solution under cooling in ice water bath, repeating for several times until pH value of the aqueous solution is neutral, extracting with ethyl acetate, separating, drying with anhydrous sodium sulfate, decolorizing with active carbon, filtering, removing solvent by rotary evaporation, crystallizing the crude product with ethanol-water in refrigerator, vacuum filtering, and adding waterAfter washing, suction drying and thorough vacuum drying, the desired target 5-bromo-6-chloro-3-indoxyl (V; 0.529g, 47% yield) was obtained.
Nuclear magnetic data for 5-bromo-6-chloro-3-indolyloctyl ester:1H-NMR(300MHz,CDCl3):δ＝7.94(s,1H,H-4)；7.68(s,1H, H-7)；7.18(d,J＝2.7Hz,1H,H-2)；2.55(t,J＝7.5Hz,2H,-CH2-)；1.80–1.63(m,2H,-CH2-)； 1.33–1.24(m,J＝13.8,13.3,5.0Hz,9H,4×CH2,-NH-)；0.83(t,J＝6.7Hz,3H,H-CH3)ppm.13C-NMR(75MHz,CDCl3):δ＝171.74(C＝O)；132.26(C-7a)；129.46(C-3a)；128.29(C-6)；121.89 (C-4)；120.25(C-2)；115.25(C-3)；113.31(C-5)；112.83(C-7)；34.23(C-2′)；31.69,29.13,28.95, 25.03,22.64(C-3′,C-4′,C-5′,C-6′,C-7′)；14.11(C-8′)ppm.HRMS:calcd.for C16H19BrClNNaO2394.0184; found 394.0180 (fig. 3 and 4)
The total yield of the four-step reaction is 26%.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611095606.3A CN106986809B (en) | 2016-12-02 | 2016-12-02 | Synthesis method of 5-bromo-6-chloro-3-indoxyl |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611095606.3A CN106986809B (en) | 2016-12-02 | 2016-12-02 | Synthesis method of 5-bromo-6-chloro-3-indoxyl |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106986809A CN106986809A (en) | 2017-07-28 |
| CN106986809B true CN106986809B (en) | 2020-03-24 |
Family
ID=59413740
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201611095606.3A Active CN106986809B (en) | 2016-12-02 | 2016-12-02 | Synthesis method of 5-bromo-6-chloro-3-indoxyl |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106986809B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110683981A (en) * | 2019-09-05 | 2020-01-14 | 湖南恒泰生物医药有限公司 | Synthesis method of 5-bromo-4-chloro-1-acetyl-3-indophenol |
| EP4196465A1 (en) * | 2020-08-17 | 2023-06-21 | Biosynth AG | Polymorphs of 5-bromo-6-chloro-3-indoxyl caprylate |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101142194A (en) * | 2005-03-14 | 2008-03-12 | 特兰斯泰克制药公司 | Benzazole derivatives, compositions, and methods of use as b-secretase inhibitors |
| CN102827918A (en) * | 2012-08-27 | 2012-12-19 | 广东环凯微生物科技有限公司 | Chromogenic medium for detecting salmonella |
| CN103145605A (en) * | 2013-02-27 | 2013-06-12 | 广东省微生物研究所 | Method for synthesizing 1-acetyl-halo-indolyl-3-acetate |
| CN105658642A (en) * | 2013-10-25 | 2016-06-08 | 蓝图药品公司 | Inhibitors of fibroblast growth factor receptor |
-
2016
- 2016-12-02 CN CN201611095606.3A patent/CN106986809B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101142194A (en) * | 2005-03-14 | 2008-03-12 | 特兰斯泰克制药公司 | Benzazole derivatives, compositions, and methods of use as b-secretase inhibitors |
| CN102827918A (en) * | 2012-08-27 | 2012-12-19 | 广东环凯微生物科技有限公司 | Chromogenic medium for detecting salmonella |
| CN103145605A (en) * | 2013-02-27 | 2013-06-12 | 广东省微生物研究所 | Method for synthesizing 1-acetyl-halo-indolyl-3-acetate |
| CN105658642A (en) * | 2013-10-25 | 2016-06-08 | 蓝图药品公司 | Inhibitors of fibroblast growth factor receptor |
Non-Patent Citations (4)
| Title |
|---|
| A simple and robust preparation of N-acetylindoxyls: precursors for indigogenic substrates;Michael N. Gandy et al.;《Organic & Biomolecular Chemistry》;20141110;第13卷(第3期);第905-908页 * |
| An improved synthesis of 1-acetyl-1H-indol-3-yl acetates;Gilbert Kirsch et al.;《Journal of Heterocyclic Chemistry》;20090313;第44卷(第1期);第273-275页 * |
| Studies in enzyme cytochemistry. II. Synthesis of indigogenic substrates for esterases;S. J. Holt and P. W. Sadler;《Proceedings of the Royal Society of London, Series B: Biological Sciences》;19580408;第148卷(第933期);第481-494页 * |
| Synthesis of indigogenic substrates. Investigation of Salmonella esterase activity;A Agban et al.;《European Journal of Medicinal Chemistry》;20040507;第25卷(第8期);第697-699页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106986809A (en) | 2017-07-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106866553B (en) | Synthesis method of Favipiravir | |
| JP6201595B2 (en) | Process for producing 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxin | |
| CN108424388A (en) | A kind of preparation method of chronic anaemia drug | |
| CN106117216B (en) | A kind of method of atmospheric synthesis 6H- iso-indoles [2,1-a] indoles -6- ketone compounds | |
| CN108467360B (en) | Preparation method and intermediate of apatinib | |
| CN104262318A (en) | Method for preparing olopatadine hydrochloride | |
| CN101367760A (en) | The synthetic method of 2-chloronicotinic acid | |
| CN112679420A (en) | Preparation method of 2,5-dibromopyridine | |
| CN106986809B (en) | Synthesis method of 5-bromo-6-chloro-3-indoxyl | |
| CN104774226A (en) | Preparation method of saccharose-6-ethyl ester | |
| CN107162973B (en) | Intramolecular Decarboxylation Coupling to Construct C-N Bonds to Synthesize Acridone Derivatives | |
| CN105622380B (en) | Preparation method of apremilast and intermediate thereof | |
| CN107188875B (en) | Preparation method and intermediate of substituted phthalide compound | |
| CN114685485A (en) | Synthesis method of pyridylimidazole thiopropionic acid anti-gout compound | |
| CN108299466B (en) | A kind of improved dolutegravir synthetic method | |
| CN102775425A (en) | Method for preparing Boc-Cefcapene through one-pot boiling | |
| CN113004236B (en) | A method for synthesizing 3-methylenebenzofuran-1(3H)-ketones | |
| CN101506141A (en) | 2-(4-methoxycarbonylmethylphenoxymethyl)benzoic acid methyl ester and method for producing the same | |
| CN106866608A (en) | A kind of preparation method of the dihydrocoumarin derivative of fluoro 3,4 | |
| TWI725710B (en) | SYNTHESIS OF 3-BROMO-5- (2-ETHYLIMIDAZO [1,2a] PYRIDINE-3-CARBONYL) -2-HYDROXYBENZONITRILE | |
| CN110563721A (en) | Preparation method of azasetron hydrochloride | |
| CN109836383B (en) | Method for preparing 3, 4-dihydroquinoline-2 (1H) -ketone compound | |
| JP6260385B2 (en) | Method for producing 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxin-5,7-dicarboxylic acid dialkyl ester | |
| CN106883227A (en) | The method that ergometrine is prepared by ergot fermentation waste | |
| CN117024423A (en) | Synthetic method of 3, 4-dihydro-isocoumarin-beta-carboline hybrid and analogue thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |