CN106986809A - A kind of synthetic method of the indoles monooctyl ester of 5 bromine, 6 chlorine 3 - Google Patents
A kind of synthetic method of the indoles monooctyl ester of 5 bromine, 6 chlorine 3 Download PDFInfo
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- CN106986809A CN106986809A CN201611095606.3A CN201611095606A CN106986809A CN 106986809 A CN106986809 A CN 106986809A CN 201611095606 A CN201611095606 A CN 201611095606A CN 106986809 A CN106986809 A CN 106986809A
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- 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
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Abstract
The invention discloses a kind of synthetic method of the indoles monooctyl ester of 5 bromine, 6 chlorine 3, it is characterized in that, the aminobenzoic acid of 4 chlorine 2 and N bromo-succinimides are obtained into the aminobenzoic acid of 5 bromine, 4 chlorine 2 by bromo-reaction, the aminobenzoic acid of 5 bromine, 4 chlorine 2 obtains N (carboxyl of 4 bromine, 5 chlorine 2) phenylglycine with sodium chloroacetate by nucleophilic substitution, N (carboxyl of 4 bromine, 5 chlorine 2) phenylglycine obtains the indoles ethyl ester of 1 acetyl group, 5 bromine, 6 chlorine 3 through being cyclized decarboxylic reaction again, the indoles ethyl ester of 1 acetyl group, 5 bromine, 6 chlorine 3 obtains the indoles monooctyl ester of 5 bromine, 6 chlorine 3 with the reaction of caprylyl chloride selective esterification.The synthetic method of the indoles monooctyl ester of 5 bromine, 6 chlorine 3 of the present invention, its efficient, safety and environmental protection, reaction gross production rate are of a relatively high, therefore can be used for the extensive synthesis of the indoles monooctyl ester of 5 bromine, 6 chlorine 3.
Description
Technical field：
The invention belongs to organic synthesis and biological analysis detection technique field, and in particular to a kind of chloro- 3- Yin of the bromo- 6- of 5-
The synthetic method of diindyl monooctyl ester.
Background technology：
Holt et al. (Proc.R.Soc.B, 1958,148,481-494) was once reported by with halo aniline, adjacent amino
Benzoic acid, N- (2- carboxyls) three kinds of compounds of phenylglycine substituent, as starting material, have synthesized one by different routes
1- acetyl group -3- indoles the ethyl esters of serial different substitutions, then further synthesize different substituted acetic acid esterases colour developing bottoms
Thing.Wherein, the synthesis of the chloro- 3- indoles ethyl esters of the bromo- 6- of 5- is related to：N- (the chloro- 2- carboxyls of 5-) phenylglycine is in bromine/second
Aromatic ring bromo-reaction (yield is 78%) occurs under the conditions of acid, obtained N- (the chloro- 2- carboxyls of the bromo- 5- of 4-) phenylglycine exists
Cyclisation decarboxylic reaction (yield is 42%), obtained 1- acetyl group -5- occur under acetic anhydride/acetic acid sodium/heated reflux condition
The bromo- chloro- 3- indoles ethyl esters of 6- first hydrolyze the whole acetyl group of removing, and occurring esterification with acetic anhydride to reselection, (yield is
42%)；This three-step reaction gross production rate is 14%, as shown in formula 1.
Rodr í guez-Dom í nguez et al. (J.Heterocycl.Chem., 2007,44,273-275) once reports 1-
Another synthetic method of the chloro- 3- indoles ethyl esters of the bromo- 6- of acetyl group -5-, i.e., with 2,4- dichlorobenzoic acids for initiation material, first
Bromo-reaction (yield is 95%), obtained bromo- 2, the 4- dichloro-benzenes of 5- occur under bromine/chlorosulfonic acid/elemental sulfur/heating condition
Formic acid is in glycine/potassium carbonate/copper powder/N,N-dimethylformamide (DMF)/is heated to reflux lower generation Liv Ullmann (Ullmann)
Condensation reaction (yield 71%), obtained N- (the chloro- 2- carboxyls of the bromo- 5- of 4-) phenylglycine is in acetic anhydride/acetic acid sodium/heating
Cyclisation decarboxylic reaction (yield is 64%) occurs under counterflow condition to finally give；This three-step reaction gross production rate is 43%, such as formula
Shown in 2.
Gandy et al. (Org.Biomol.Chem., 2015,13,905-908) reports 1- acetyl group -5- again in recent years
The novel synthesis of the bromo- chloro- 3- indoles ethyl esters of 6-.This method is sequentially passed through and salt using the chloro- 2- fluorobenzaldehydes of 4- as starting material
Dehydration (yield is 84%) after the nucleophilic addition of sour azanol, (yield is with the condensation reaction of ethyl aminoacetate hydrochloride
72%), with ammonium bromide, the aromatic ring bromo-reaction (yield is 81%) of hydrogen peroxide, hydrolysis (yield is 95) and last pass
(yield is 88% to ring decarboxylic reaction；Note：Without recrystallization) and obtain object；This five step reaction gross production rate is 41%, such as
Shown in formula 3.
Agban et al. (Eur.J.Med.Chem., 1990,25,697-699) reports the conjunction of a variety of 3- indoxyl carboxylic acid esters
Into, but it is merely related to by a variety of 1- acetyl group -3- indoles ethyl esters (but without the chloro- 3- indoles ethyl esters of the bromo- 6- of 1- acetyl group -5-)
To the single step reaction of a variety of 3- indoxyl carboxylic acid esters, and the rate of output is not all given, also do not synthesize the chloro- 3- indoles of the bromo- 6- of 5- pungent
Ester.
There is problems with above-mentioned study on the synthesis：The synthetic route of the chloro- 3- indoles monooctyl esters of the bromo- 6- of 5- and its specific preparation
Process has no report；For the synthesis of intermediate, during bromo-reaction, using high toxicity bromine as brominated reagent, acetic acid, chlorine
Sulfonic acid equal solvent hardly possible is reclaimed, and the pollutant for being easily caused generation is more；Some other step reactions or intermediate reaction route total yield
Rate is relatively low etc..
The content of the invention：
It is an object of the invention to provide a kind of than more efficient and the of a relatively high bromo- 6- of 5- of safety and environmental protection, reaction gross production rate
The synthetic method of chloro- 3- indoles monooctyl ester.The chloro- 3- indoles monooctyl esters of the bromo- 6- of 5- are currently typically used as inspection in microorganism detection field
Survey the chromogenic substrate (or colour developing probe) of the salmonella containing specific sad esterase.
The synthetic method of the chloro- 3- indoles monooctyl esters of the bromo- 6- of 5- of the present invention, it is characterised in that comprise the following steps：
The chloro- 2- aminobenzoic acids of 4- and N- bromo-succinimides are obtained into the chloro- 2- amino of the bromo- 4- of 5- by bromo-reaction
Benzoic acid, the chloro- 2- aminobenzoic acids of the bromo- 4- of 5- obtain N- (the chloro- 2- carboxylics of the bromo- 5- of 4- with sodium chloroacetate by nucleophilic substitution
Base) phenylglycine, N- (the chloro- 2- carboxyls of the bromo- 5- of 4-) phenylglycine again through be cyclized decarboxylic reaction obtain 1- acetyl group -5-
The bromo- chloro- 3- indoles ethyl esters of 6-, the chloro- 3- indoles ethyl esters of the bromo- 6- of 1- acetyl group -5- obtain 5- with the reaction of caprylyl chloride selective esterification
The bromo- chloro- 3- indoles monooctyl esters of 6-.
Its specific synthetic route is shown below：
Bromo-reaction, nucleophilic substitution, cyclisation decarboxylic reaction and caprylyl chloride selective esterification are reacted, and each step reaction is produced
Rate is followed successively by 98%, 84%, 68% and 47%, and this four-step reaction gross production rate is 26%.
Wherein, the solvent acetonitrile and used in bromo-reaction is utilized because low boiling is easily reclaimed and repeated, and NBS used is solid
Body brominated reagent, its corresponding accessory substance is succimide；With in background technology, using one of bromine and byproduct of reaction
Compared for HBr bromo-reaction, the obvious more safety and environmental protection, and yield is also very high of bromo method of the invention.
For this single step reaction of nucleophilic displacement of fluorine sodium chloroacetate, present invention addition KI is catalyst, can promote reaction rate more
It hurry up.For cyclisation decarboxylation and last selective esterification this two-step reaction, the present invention, which is also made that, corresponding to be conducive to improving anti-
The change measure of yield is answered, such as suitably regulation rate of charge, controlling reaction temperature and time, change post-reaction treatment.
The synthetic method of the chloro- 3- indoles monooctyl esters of the bromo- 6- of 5- of the present invention, its efficient, safety and environmental protection, reaction gross production rate are relative
It is higher, therefore can be used for the extensive synthesis of the chloro- 3- indoles monooctyl esters of the bromo- 6- of 5-.
Brief description of the drawings
Fig. 1 is the H modal datas of the chloro- 3- indoles ethyl esters of the bromo- 6- of 1- acetyl group -5-；
Fig. 2 is the C modal datas of the chloro- 3- indoles ethyl esters of the bromo- 6- of 1- acetyl group -5-；
Fig. 3 is the H modal datas of the chloro- 3- indoles monooctyl esters of the bromo- 6- of 5-；
Fig. 4 is the C modal datas of the chloro- 3- indoles monooctyl esters of the bromo- 6- of 5-.
Embodiment：
Following examples are that the present invention is further illustrated, rather than limitation of the present invention.
Embodiment 1：
The synthetic route of the present embodiment is shown below：
(1) synthesis of the chloro- 2- aminobenzoic acids (II) of the bromo- 4- of 5-
The chloro- 2- aminobenzoic acids (I of 4- are added to 500mL single necked round bottom flask；20.00g, 116.6mmol), then add
Acetonitrile (300mL), quick stirring is sub- to be repeatedly slowly added into N- bromos succinyl on a small quantity at room temperature in ecru suspension
Amine (NBS；20.75g, 116.6mmol), continue stirring reaction 1h after adding, then boiled off in 45 DEG C of water-bath backspins except solvent,
Water stirring is added, suction filtration, washing, in vacuum drying at 60 DEG C, obtains the chloro- 2- aminobenzoic acids of the required bromo- 4- of object 5-
(98%) II, 28.62g, yield be.
The nuclear magnetic data of the chloro- 2- aminobenzoic acids of the bromo- 4- of 5-：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- (the chloro- 2- carboxyls of the bromo- 5- of 4-) phenylglycine (III)
The chloro- 2- aminobenzoic acids (II of the bromo- 4- of 5- are added to bis- mouthfuls of round-bottomed flasks of 150mL；5.00g, 19.96mmol),
NaOH (0.83g, 20.74mmol) and water (40mL), stir it is complete to solid dissolving, sequentially add KI (0.34g,
2.05mmol), sodium chloroacetate (4.83g, 41.47mmol), uses Na2CO3(2mol/L) solution adjusts pH value to 7~8, is heated to reflux
Lower reaction, during which constantly by adding Na2CO3Solution (2mol/L) adjusts pH value to 7~8, when reacting liquid pH value in 45min not
During change, stop heating and stir, after cooling, add the dilution of 40mL water, it is 4 that pH value is then acidified to concentrated hydrochloric acid, and suction filtration is cold
Water washing, drains after vacuum drying at 60 DEG C, is then removed and remained and unreacted substrate raw material on a small quantity with acetonitrile extraction,
Object N- (the chloro- 2- carboxyls of the bromo- 5- of 4-) phenylglycine (III needed for obtaining；5.20g, yield 84%).
The nuclear magnetic data of N- (the chloro- 2- carboxyls of the bromo- 5- of 4-) 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 the chloro- 3- indoles ethyl esters (IV) of the bromo- 6- of 1- acetyl group -5-
Weigh N- (the chloro- 2- carboxyls of the bromo- 5- of 4-) phenylglycine (III；5.000g, 16.21mmol), anhydrous sodium acetate
(5.318g, 64.83mmol, 4.0equiv.) is placed in bis- mouthfuls of round-bottomed flasks of 150mL, is added acetic anhydride (75mL), is placed in
In about 150 DEG C of oil bath of heating in advance, in stirring reaction at 135~140 DEG C untill no longer carbon dioxide is produced (about
25min), then take out, cool down, add the mixture of ice and water of more amount, stir or stand in ice-water bath to grease disappearance
Untill, suction filtration, saturated sodium bicarbonate is washed to neutrality, then is fully washed with water, is drained, a small amount of cold methanol washing, alcohol-water
After recrystallization, fully vacuum drying, the chloro- 3- indoles ethyl esters (IV of the bromo- 6- of object 1- acetyl group -5- needed for obtaining；3.644g,
68%) yield is.
The nuclear magnetic data of the chloro- 3- indoles ethyl esters of the bromo- 6- of 1- acetyl group -5-：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 C12H9BrClNNaO3:351.9347；
Found 351.9349. (Fig. 1 and Fig. 2)
(4) synthesis of the chloro- 3- indoles monooctyl esters (V) of the bromo- 6- of 5-
Weigh the chloro- 3- indoles ethyl esters (IV of the bromo- 6- of 1- acetyl group -5-；0.992g, 3.00mmol) it is placed in many mouthfuls of round bottoms of 50mL
In flask, NaOH solution (2mol/L, 16.5mL) is added, after abundant deoxygenation, in containing N2The lower heating reflux reaction of protection is straight
To solid it is complete molten and untill obtaining uniform dark brown opaque transparent liquid, then cool down one after the meeting, be transferred in ice-water bath and cool down,
Quick stirring is lower to be added after caprylyl chloride (2.9mL), reaction 0.5h, and stopping is passed through N2, terminate reaction.The upper strata aqueous solution is poured off,
Add 1mol/L Na2CO3Solution is simultaneously stirred under ice-water bath cooling, is repeated several times, untill pH value of water solution is neutrality,
Extracted with ethyl acetate, point liquid, anhydrous sodium sulfate drying, activated carbon decolorizing, filtering, revolving removes solvent, by crude product second
Alcohol-water is crystallized in refrigerator, suction filtration, washing, is drained, after fully vacuum drying, the chloro- 3- of the bromo- 6- of object 5- needed for obtaining
Indoles monooctyl ester (V；47%) 0.529g, yield is.
The nuclear magnetic data of the chloro- 3- indoles monooctyl esters of the bromo- 6- of 5-：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 C16H19BrClNNaO2: 394.0184；Found 394.0180. (Fig. 3 and Fig. 4)
Four-step reaction gross production rate is 26%.
Claims (1)
1. a kind of synthetic method of the chloro- 3- indoles monooctyl esters of the bromo- 6- of 5-, it is characterised in that by the chloro- 2- aminobenzoic acids of 4- and N- bromines
For succimide the chloro- 2- aminobenzoic acids of the bromo- 4- of 5-, the chloro- 2- aminobenzoic acids of the bromo- 4- of 5- and chlorine are obtained by bromo-reaction
Sodium acetate obtains N- (the chloro- 2- carboxyls of the bromo- 5- of 4-) phenylglycine, N- (the chloro- 2- carboxyls of the bromo- 5- of 4-) by nucleophilic substitution
Phenylglycine obtains the chloro- 3- indoles ethyl esters of the bromo- 6- of 1- acetyl group -5-, the bromo- 6- of 1- acetyl group -5- through being cyclized decarboxylic reaction again
Chloro- 3- indoles ethyl ester obtains the chloro- 3- indoles monooctyl esters of the bromo- 6- of 5- with the reaction of caprylyl chloride selective esterification.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
| WO2022038120A1 (en) * | 2020-08-17 | 2022-02-24 | Biosynth Ag | Polymorphs of 5-bromo-6-chloro-3-indoxyl caprylate |
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Cited By (2)
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| 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 |
| WO2022038120A1 (en) * | 2020-08-17 | 2022-02-24 | Biosynth Ag | Polymorphs of 5-bromo-6-chloro-3-indoxyl caprylate |
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