CN103145605A - Method for synthesizing 1-acetyl-halo-indolyl-3-acetate - Google Patents
Method for synthesizing 1-acetyl-halo-indolyl-3-acetate Download PDFInfo
- Publication number
- CN103145605A CN103145605A CN2013100623544A CN201310062354A CN103145605A CN 103145605 A CN103145605 A CN 103145605A CN 2013100623544 A CN2013100623544 A CN 2013100623544A CN 201310062354 A CN201310062354 A CN 201310062354A CN 103145605 A CN103145605 A CN 103145605A
- Authority
- CN
- China
- Prior art keywords
- carboxyl
- phenylglycocoll
- bromo
- chloro
- reaction
- 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.)
- Pending
Links
Landscapes
- Indole Compounds (AREA)
Abstract
The invention discloses a method for synthesizing 1-acetyl-halo-indolyl-3-acetate. According to the method, ortho-aminobenzoic acid with a general formula (II) and a chloride of ortho-aminobenzoic acid which serve as starting raw materials react with ClCH2COOH, NaOH, Na2CO3 and a catalyst KI (or NaI or the like) to produce N-(2-carboxyl)phenylglycine with a general formula (III) and a chloride of N-(2-carboxyl)phenylglycine, N-(2-carboxyl)phenylglycine bromine of a general formula (IV) and a chloride of N-(2-carboxyl)phenylglycine bromine are produced in a manner that N-(2-carboxyl)phenylglycine and the chloride of N-(2-carboxyl)phenylglycine react with N-bromosuccinimide (NBS), CH3OH, H2O and a catalyst, namely ammonium nitrate (or strong acids and weak-base salts, such as ammonium chloride, ammonium sulfate, hydrochloric acid, p-toluenesulfonic acid (p-TSA) and sulfuric acid, or protonic acid), and N-(2-carboxyl)phenylglycine bromine and the chloride of N-(2-carboxyl)phenylglycine bromine react with Ac2O and anhydrous AcNa to produce 1-acetyl-halo-indolyl-3-acetate. The method has the advantages of being safer, more environment-friendly, more time-saving, more convenient in operation, and the like.
Description
Technical field
The invention belongs to the field of chemical synthesis, be specifically related to the synthetic method of 1-ethanoyl-halogeno indole base-3-acetic ester.
Background technology:
Indolol claims again 3-hydroxyindole, and with 3-indolone tautomerism, spontaneous dimerization becomes indigo in air.The indolol chromogenic substrate is a very important chromogenic substrate of class, particularly has a wide range of applications aspect microorganism detection.They are to form with the indirect condensation of enzyme substrates by producing the chromogen indolol, can discharge when it is subjected to the target enzyme hydrolytic action occur under indolol and aerial dioxygen oxidation two molecules be coupled to water insoluble, thermostability is high, the dimeric dyes that develops the color.Different indolol produces chromogen, and its colour developing result is also different, and wherein widespread use has 5-bromo-4-chloro-3-indolol, a 5-bromo-3-indolol etc.Because the indolol substituent has the advantages such as high sensitivity, low toxicity, color developing are good as producing chromogen, they are widely used in synthesizing various chromogenic substrates.
Because indolol and substituent thereof can not stable existences; therefore be to react with their derivative participation when synthesis of indole phenol chromogenic substrate; as 1-ethanoyl-5-bromo-4 chloro-indole base-3-acetic ester etc.; these materials also can be used as the intermediate of synthetic good coloured, fluorescence dye except above effect.For synthesizing of 1-ethanoyl-5-bromo-4 chloro-indole base-3-acetic ester and 1-ethanoyl-5-bromo indole base-these two kinds of intermediates of 3-acetic ester, Holt etc. once reported with the 3-chloroaniline and obtained through the reaction of five steps, catalyst-free during the condensation chloroacetate reaction wherein, reaction is with duration (6～72h); Bromo-reaction adopts be take acetic acid as solvent, bromine is the synthetic method of brominated reagent, the dangerous property of this method is large, produce strong acid HBr pollutent, the high shortcomings such as aftertreatment trouble such as recoverys that cause of acetic acid boiling point, scale one is large, these shortcomings are just more obvious; Final step is after reaction (be Heumann reaction) under diacetyl oxide, sodium acetate condition, and aftertreatment adopts vacuum rotary steam to obtain crude product, makes operation power consumption, relatively inconvenient etc. because the diacetyl oxide boiling point is high.And about their improvement or new synthesis technique, particularly 1-ethanoyl-5-bromo-4 chloro-indole base-3-acetic ester have had not yet to see report.
Summary of the invention:
The objective of the invention is the deficiency for above-mentioned preparation method's existence, provide a kind of as leading to the new synthetic method of the 1-ethanoyl as shown in formula I-halogeno indole base-3-acetic ester.
The synthetic method of the 1-ethanoyl-halogeno indole base-3-acetic ester as shown in logical formula I of the present invention is characterized in that, comprises the following steps:
(a) with anthranilic acid or its chloro thing as shown in logical formula II, with Mono Chloro Acetic Acid or sodium chloroacetate generation nucleophilic substitution reaction, obtain N-(2-carboxyl) phenylglycocoll or its chloro thing shown in logical formula III;
be specially: anthranilic acid or its chloro thing and Mono Chloro Acetic Acid or sodium chloroacetate are mixed with solid form according to mol ratio 1:1 ~ 2.5, add the neutralization of sodium hydroxide or potassium hydroxide solution, regulate pH value to 6.5～9.0 with salt of wormwood or sodium carbonate solution again, add again the potassiumiodide of anthranilic acid or its chloro thing 5 ~ 10% molar equivalents or sodium iodide as catalyzer, heating reflux reaction, utilize salt of wormwood or sodium carbonate solution to control the pH value of reaction system 6.5～9.0, until the pH value when constant in 20min at least reaction finish, purifying obtains N-(2-carboxyl) phenylglycocoll or its chloro thing shown in logical formula III,
(b) will lead to (2-carboxyl) phenylglycocoll of the N-shown in formula III or its chloro thing and just obtain N-(4-bromo-3-chloro-2-carboxyl) phenylglycocoll or N-(the 4-bromo-2-carboxyl) phenylglycocoll shown in logical formula IV through the aromatic ring bromo-reaction;
Be specially: take the N-bromo-succinimide as brominated reagent, N-(2-carboxyl) phenylglycocoll or its chloro thing and N-bromo-succinimide batching mol ratio are 1:1 ~ 1.1, first N-(2-carboxyl) phenylglycocoll or its chloro thing are mixed with solid form with the N-bromo-succinimide, after ice-water bath is cooling, then add while stirring the mixed solution of the cooling methyl alcohol of ice-water bath, water, catalyzer; Perhaps first the N-bromo-succinimide is dissolved in the solution of methyl alcohol, water and catalyzer, then the limit stirring is added in the cooling N-of ice bath (2-carboxyl) phenylglycocoll or its chloro thing; Perhaps first N-(2-carboxyl) phenylglycocoll or its chloro thing and cold methanol, cold water mix are stirred, then add catalyzer, the cooling insulation of ice-water bath, more under agitation add once the N-bromo-succinimide; React 10 ~ 30min under the environment of 0 ~ 15 ℃, then go to and continue reaction under 20 ~ 30 ℃ of environment to the reaction end, obtain N-(4-bromo-3-chloro-2-carboxyl) phenylglycocoll or N-(the 4-bromo-2-carboxyl) phenylglycocoll shown in logical formula IV after purifying;
The consumption of described methyl alcohol is: 35～50ml/g N-(2-carboxyl) phenylglycocoll or its chloro thing, the consumption of described water is 10 ~ 47% of methanol usage volume, described catalyzer comprises hydrochloric acid, toluenesulphonic acids (p-TSA), sulfuric acid, ammonium nitrate, ammonium chloride, ammonium sulfate, with respect to N-(2-carboxyl) phenylglycocoll or its chloro thing, the consumption of hydrochloric acid, toluenesulphonic acids (p-TSA) or sulfuric acid is all 2.9 ~ 8% molar equivalents, and the consumption of ammonium nitrate, ammonium chloride, ammonium sulfate is all 100 ~ 110% molar equivalents;
(c) N-(the 4-bromo-3-chloro-2-carboxyl) phenylglycocoll as shown in logical formula IV or N-(4-bromo-2-carboxyl) phenylglycocoll are obtained as leading to the 1-ethanoyl as shown in formula I-halogeno indole base-3-acetic ester through the Heumann reaction;
be specially: N-(4-bromo-3-chloro-2-carboxyl) phenylglycocoll or N-(4-bromo-2-carboxyl) phenylglycocoll and anhydrous sodium acetate are joined in the reaction flask that contains diacetyl oxide, the mass ratio of N-(4-bromo-3-chloro-2-carboxyl) phenylglycocoll or N-(4-bromo-2-carboxyl) phenylglycocoll and anhydrous sodium acetate is 1:1, the diacetyl oxide consumption is 10 ~ 20ml/g N-(4-bromo-3-chloro-2-carboxyl) phenylglycocoll or N-(4-bromo-2-carboxyl) phenylglycocoll, first oil bath is heated to 135～145 ℃ in advance, putting into reaction flask reacts keeping to bathe under temperature again, until till carbon dioxide no longer produces, reaction finishes, the ice-water bath product, after disappearing, oily liquids just can collect crude product, through washing, recrystallization namely obtains as leading to the 1-ethanoyl as shown in formula I-halogeno indole base-3-acetic ester,
R in above-mentioned formula I, (II), (III) and (IV)
1Represent Cl or H, R
2Represent H.
The present invention selects as leading to the anthranilic acid as shown in formula II or its chloro thing as starting raw material, for this raw material, and at present domestic existing many manufacturer production, not only reliable in quality, and price is also relatively cheap.This raw material can with Mono Chloro Acetic Acid or sodium chloroacetate generation nucleophilic substitution reaction, just obtain logical formula III N-(2-carboxyl) phenylglycocoll or its chloro thing, thereby continue the reaction of back.
For the nucleophilic substitution reaction of step (a), the anthranilic acid shown in logical formula II or the input mol ratio of its chloro thing and Mono Chloro Acetic Acid or sodium chloroacetate can be 1:1～2.5, are preferably 1:1.5～2; Reaction solvent adopts water; Alkali used can be sodium hydroxide, potassium hydroxide, salt of wormwood, sodium carbonate etc., adopt mixed base in the present invention, acid appropriate to the occasion employing hydroxide bases namely neutralizes, can avoid producing the carbonic acid gas bubble, and can adopt carbonate to control certain pH value in reaction process, can produce the bubble situation by observation like this and add alkali; In reaction process, the pH of mixed value can be controlled in 6.5～9.0, is suitably 7.0～8.0; Add potassiumiodide or sodium iodide etc. as catalyzer, can accelerate extent of reaction, consumption can be anthranilic acid or its chloro thing 5%～10% molar equivalent, just can finish when reacting constant in 20min to the pH value, the reaction required time generally is no more than 2.5h, compare the background technology of not using catalyzer, can shorten a few hours; Temperature of reaction is reflux, and namely the solvent boiling point to the temperature between the reaction mixture boiling, approaches boiling and be suitably, and is beneficial to observe the bubble situation of producing; The situation of feeding intake can be first will lead to the anthranilic acid shown in formula II or its chloro thing mixes with solid form with Mono Chloro Acetic Acid or sodium chloroacetate, the limit is stirred and is slowly added the alkali lye neutralization again, also can will lead to the anthranilic acid shown in formula II or its chloro thing first neutralizes with alkali lye, add again sodium chloroacetate, and then with the lye pH adjustment value to slight alkalinity, add at last catalyzer.After reaction finishes, during the acidification reaction mixed solution, available concentrated hydrochloric acid or its diluent, the pH value of acidifying is 2.0～2.5.For above-mentioned nucleophilic substitution reaction, particularly N-(3-chloro-2-carboxyl) phenylglycocoll is synthetic, and the present invention can be more than 50% by the maximum output that obtains at present N-(2-carboxyl) phenylglycocoll shown in logical formula III or its chloro thing after optimizing.
aromatic ring bromo-reaction for step (b), the present invention has groped the bromo method that makes new advances, that is: take N-bromo-succinimide (NBS) as brominated reagent, methyl alcohol is as solvent, catalyzer can be hydrochloric acid, tosic acid (p-TSA), sulfuric acid, ammonium nitrate, ammonium chloride, ammonium sulfate etc., what wherein catalytic effect was best is ammonium nitrate, and ammonium sulfate is poorer due to the relatively bad catalytic effect that causes of solvability, if and add suitable quantity of water, can further improve reaction yield, on feeding intake, N-(2-carboxyl) phenylglycocoll shown in logical formula III or its chloro thing and NBS mol ratio are 1:1～1.1, methanol usage can be N-(2-carboxyl) phenylglycocoll or its chloro thing shown in the logical formula III of 35～50 times (ml/g), water consumption can be 10%～47% of quantity of methyl alcohol, with respect to N-(2-carboxyl) phenylglycocoll or its chloro thing, strong protonic acid (hydrochloric acid, toluenesulphonic acids (p-TSA), sulfuric acid) consumption is 2.9%～8% molar equivalent, strong acid weak base ammonium salt (ammonium nitrate, ammonium chloride, ammonium sulfate) consumption is i.e. 1.0～1.1 molar equivalents of 100%～110%(), for temperature of reaction, initial appropriate to the occasion employing low temperature, as ice-water bath, but should not be over 15 ℃, then reaction 10～30min goes under room temperature and proceeds, and room temperature can be 20～30 ℃, wherein suitablely during as catalyzer with strong protonic acid react at relatively low temperature, suitablely during take the strong acid weak base ammonium salt as catalyzer react at relatively high temperature, the situation of feeding intake can be first will lead to (2-carboxyl) phenylglycocoll of the N-shown in formula III or its chloro thing mixes with solid form with NBS, after ice-water bath is cooling, add while stirring the more cooling methyl alcohol of ice-water bath, water, catalyst mixed liquid, perhaps first prepare the methyl alcohol of NBS, water, catalyst mixed liquid, the limit is stirred and is added in cooling (III) again, perhaps first with N-(2-carboxyl) phenylglycocoll or its chloro thing and cold methanol, cold water mix stirs, then add catalyzer, the cooling insulation of ice-water bath, under agitation add once again the N-bromo-succinimide.use the present invention to carry out N-(the 4-bromo-3-chloro-2-carboxyl) phenylglycocoll that bromo-reaction obtains, N-(4-bromo-2-carboxyl) phenylglycocoll, its maximum output can reach more than 53% respectively at present, more than 80%, say on the whole, aromatic ring bromo method of the present invention has not only guaranteed productive rate, and because the danger of NBS is more much lower than bromine, though the methanol solvate consumption is relatively many, but be easy to reclaim, can reuse, product separation is easy, to catalyzer, the processing of by product succinimide is convenient, therefore aromatic ring bromo method of the present invention has safety and environmental protection, the advantages such as easy handling.
Reaction just obtains the 1-ethanoyl shown in the logical formula I of target compound-halogeno indole base-3-acetic ester through Heumann for will lead to (the 4-bromo-3-chloro-2-carboxyl) phenylglycocoll of the N-shown in formula IV or N-(the 4-bromo-2-carboxyl) phenylglycocoll of step (c).This reaction is carried out under the condition that contains decarboxylation, dewatering agent diacetyl oxide, catalyzer anhydrous sodium acetate, reflux.On feeding intake, N-(4-bromo-3-chloro-2-carboxyl) phenylglycocoll shown in logical formula IV or N-(4-bromo-2-carboxyl) phenylglycocoll and anhydrous sodium acetate mass ratio are 1:1, and the diacetyl oxide consumption can be N-(4-bromo-3-chloro-2-carboxyl) phenylglycocoll or N-(the 4-bromo-2-carboxyl) phenylglycocoll shown in the logical formula IV of 10～20 times (ml/g).The present invention is when heat treated, employing is heated to 135～145 ℃ of left and right in advance with oil bath, putting into reaction flask reacts keeping to bathe under temperature again, until till carbon dioxide no longer produces, so not only be conducive to observe the bubble situation of producing, and make the reaction times shorter and stable, generally at 10～17min; When aftertreatment, adopt to add frozen water and to stir or standing for some time under ice-water bath, treat that oily liquids disappears just can collect crude product, get final product through washing, recrystallization.Obtain like this 1-ethanoyl-5-bromo-4-chloro-indole base-3-acetic ester, 1-ethanoyl-5-bromo indole base-3-acetic ester productive rate is respectively more than 64%, more than 71%, and operation is easy.
This shows, of the present invention not only productivity ratio is higher, and operation is easy as leading to the synthetic method of the 1-ethanoyl as shown in formula I-halogeno indole base-3-acetic ester, and safety has broad application prospects.
Embodiment:
By the following examples foregoing of the present invention is described in further detail, but this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following example.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
Embodiment 1
(1) nucleophilic substitution reaction:
(1) N-(3-chloro-2-carboxyl) phenylglycocoll is synthetic
Take 10.00g(0.058mol) 6-chloro-2-benzaminic acid, 8.80g(0.093mol) Mono Chloro Acetic Acid, the limit mixes, the limit adds the neutralization of 100g/L sodium hydroxide solution lentamente, and with 3mol/L sodium carbonate solution adjust pH to 7.5～8.0, add the 0.50g potassiumiodide, react under reflux, during add off and on the 3mol/L sodium carbonate solution to control reacting liquid pH value 7.0～8.0, react constant in 20min to the pH value till.Add the 2g gac, stir 0.5～1h under temperature more than oil bath, suction filtration, be 2.0～2.5 with concentrated hydrochloric acid acidifying filtrate to pH value after the suitable quantity of water dilution, suction filtration is also drained, after vacuum-drying fully, obtain canescence product (N-(3-chloro-2-carboxyl) phenylglycocoll) 7.08g(productive rate: 52.9%) again.
1H-NMR(300MHz, DMSO-d
6): δ 7.203(t, 1H, 5-H, J
4or6,5=7.8Hz); δ 6.703(dd, 1H, 4-H, J
4,6=0.6Hz and J
4,5=7.8Hz); δ 6.514(dd, 1H, 6-H, J
4,6=0.6Hz and J
5,6=7.8Hz); δ 3.900(s, 2H, CH
2).
Response situation under other feed ratio, pH value, catalyst levels condition (other conditions are identical) is as table 1:
Table 1
(2) N-(2-carboxyl) phenylglycocoll is synthetic
Take 5.00g(0.036mol) anthranilic acid, 6.80g(0.058mol) sodium chloroacetate, the limit mixes, the limit adds the neutralization of 30g/L sodium hydroxide solution lentamente, and with 1mol/L sodium carbonate solution adjust pH to 7.5～8.0, add the 0.30g potassiumiodide, react under reflux, during add off and on the 1mol/L sodium carbonate solution to control reacting liquid pH value 7.0～8.0, react constant in 20min to the pH value till.Be 2.0 with concentrated hydrochloric acid acidifying filtrate to pH value, suction filtration washs with suitable quantity of water, drain, use the methanol-water recrystallization, obtain white needle-like crystals, after vacuum-drying fully, obtain product (N-(2-carboxyl) phenylglycocoll) 3.93g(productive rate: 55.3%) again.
1H-NMR（300MHz，DMSO-d
6）：δ12.625(s,2H,2COOH);δ8.133(s,1H,N-H);δ7.823(t,1H,Ph-H,J=7.2Hz);δ7.343(m,1H,Ph-H);δ7.600(m,2H,Ph-H);δ3.992(s,2H,CH
2)。
Response situation under other feed ratio, pH value, catalyst levels condition (other conditions are identical) is as table 2:
Table 2
(2) aromatic ring bromo-reaction:
(1) N-(4-bromo-3-chloro-2-carboxyl) phenylglycocoll is synthetic
Take 2.00g(0.0087mol) N-(3-chloro-2-carboxyl) phenylglycocoll, 1.63g(0.0092mol) the N-bromo-succinimide, ice bath is cooling, add while stirring prior ice-water bath cooling contain 0.70g(0.0087mol) the 30ml water of ammonium nitrate+80ml methyl alcohol mixed liquor, react 15min in ice-water bath, then remove ice-water bath, in the lower reaction 7h that continues of room temperature (20 ~ 30 ℃).After reaction finished, vacuum rotary steam is removed methyl alcohol, and was cooling, suction filtration, appropriate cold water washing is drained, after vacuum-drying fully, obtain faint yellow or yellow-white product (N-(4-bromo-3-chloro-2-carboxyl) phenylglycocoll) 1.43g(productive rate: 53.2%) again.
1H-NMR（300MHz，DMSO-d
6）：δ7.421(d,1H,5-H,J=8.4Hz)；δ6.408(d,1H,6-H,J=8.4Hz)；δ3.841(s,2H,CH
2)。
In other catalyzer and corresponding ice-water bath, the response situation (other conditions are identical) in reaction times is as table 3:
Table 3
(2) N-(4-bromo-2-carboxyl) phenylglycocoll is synthetic
Take 2.00g(0.010mol) N-(2-carboxyl) phenylglycocoll, 1.92g(0.011mol) the N-bromo-succinimide, ice bath is cooling, add while stirring prior ice-water bath cooling contain 0.82g(0.010mol) the 30ml water of ammonium nitrate+80ml methyl alcohol mixed liquor, react 15min in ice-water bath, then remove ice-water bath, in the lower reaction 7h that continues of room temperature (20 ~ 30 ℃).After reaction finished, vacuum rotary steam is removed methyl alcohol, and was cooling, suction filtration, and appropriate cold water washing is drained, then after vacuum-drying fully, obtains white product (N-(4-bromo-2-carboxyl) phenylglycocoll) 2.26g(productive rate: 80.5%).
1H-NMR（300MHz，DMSO-d
6）：δ12.968(s,2H,2COOH);δ8.142(s,1H,N-H);δ7.864(d,1H,3-H,J=2.4Hz);δ7.493(dd,1H,5-H,J
3,5=2.4Hz,J
5，6=9Hz);δ6.602(d,1H,6-H,J=9Hz);δ4.005(s,2H,CH
2)。
In other catalyzer and corresponding ice-water bath, the response situation (other conditions are identical) in reaction times is as table 4:
Table 4
(3) Heumann reaction:
(1) 1-ethanoyl-5-bromo-4-chloro-indole base-3-acetic acid ester synthesis
take 2.00g(0.0065mol) N-(4-bromo-3-chloro-2-carboxyl) phenylglycocoll, 2.00g anhydrous sodium acetate, add the 20ml diacetyl oxide, stirring reaction (approximately 15min) till no longer produce carbonic acid gas in being heated in advance the oil bath of 138～142 ℃, then take out immediately, cooling, the mixture of ice and water that adds more amount, stir in ice-water bath or standing disappear to oily matter till, suction filtration, water washing, drain, again with a small amount of cold methanol washing, ethyl alcohol recrystallization, fully obtain yellow needle-like crystal (1-ethanoyl-5-bromo-4-chloro-indole base-3-acetic ester) 1.38g(productive rate after vacuum-drying: 64.4%).
1H-NMR（300MHz，DMSO-d
6）：δ8.243(d,1H,6-H,J=9Hz);δ8.041(s,1H,2-H);δ6.676(d,1H,7-H,J=9Hz);δ2.627(s,3H,OCOCH
3);δ2.374(s,3H,NCOCH
3)。
13C-NMR（300MHz，CDCl
3）：δ168.65;δ168.29;δ133.18;δ132.88;δ130.50;δ124.42;δ122.37;δ118.55;δ116.30;δ116.24;δ23.78;δ21.04。
Response situation under other scales that feed intake (other conditions are identical) is as table 5:
Table 5
(2) 1-ethanoyl-5-bromo indole base-3-acetic acid ester synthesis
take 2.00g(0.0073mol) N-(4-bromo-2-carboxyl) phenylglycocoll, 2.00g anhydrous sodium acetate, add the 20ml diacetyl oxide, stirring reaction (approximately 11min) till no longer produce carbonic acid gas in being heated in advance the oil bath of 138～142 ℃, then take out immediately, cooling, the mixture of ice and water that adds more amount, stir in ice-water bath or standing disappear to oily matter till, suction filtration, water washing, drain, use again the methanol-water recrystallization, fully obtain yellow needle-like crystal (1-ethanoyl-5-bromo indole base-3-acetic ester) 1.53g(productive rate after vacuum-drying: 70.8%).
1H-NMR（300MHz，DMSO-d
6）：δ8.289(d,1H,7-H,J=9Hz);δ7.951(s,1H,2-H);δ7.773(d,1H,4-H,J=2.1Hz);δ7.534(dd,1H,6-H,J
6,7=9Hz,J
4,6=2.1Hz);δ2.619(s,3H,OCOCH
3);δ2.386(s,3H,NCOCH
3)。
13C-NMR（300MHz，CDCl
3）：δ168.628;δ167.694;δ133.532;δ131.449;δ129.074;δ125.188;δ120.313;δ118.187;δ117.097;δ114.344;δ23.799;δ21.029。
Response situation under other scales that feed intake (other conditions are identical) is as table 6:
Table 6
Claims (2)
1. the synthetic method of the 1-ethanoyl-halogeno indole base-3-acetic ester as shown in logical formula I, is characterized in that, comprises the following steps:
(a) with anthranilic acid or its chloro thing as shown in logical formula II, with Mono Chloro Acetic Acid or sodium chloroacetate generation nucleophilic substitution reaction, obtain N-(2-carboxyl) phenylglycocoll or its chloro thing shown in logical formula III;
be specially: anthranilic acid or its chloro thing and Mono Chloro Acetic Acid or sodium chloroacetate are mixed with solid form according to mol ratio 1:1 ~ 2.5, add the neutralization of sodium hydroxide or potassium hydroxide solution, regulate pH value to 6.5～9.0 with salt of wormwood or sodium carbonate solution again, add again the potassiumiodide of anthranilic acid or its chloro thing 5 ~ 10% molar equivalents or sodium iodide as catalyzer, heating reflux reaction, utilize salt of wormwood or sodium carbonate solution to control the pH value of reaction system 6.5～9.0, until the pH value when constant in 20min at least reaction finish, purifying obtains N-(2-carboxyl) phenylglycocoll or its chloro thing shown in logical formula III,
(b) will lead to (2-carboxyl) phenylglycocoll of the N-shown in formula III or its chloro thing and just obtain N-(4-bromo-3-chloro-2-carboxyl) phenylglycocoll or N-(the 4-bromo-2-carboxyl) phenylglycocoll shown in logical formula IV through the aromatic ring bromo-reaction;
Be specially: take the N-bromo-succinimide as brominated reagent, N-(2-carboxyl) phenylglycocoll or its chloro thing and N-bromo-succinimide batching mol ratio are 1:1 ~ 1.1, first N-(2-carboxyl) phenylglycocoll or its chloro thing are mixed with solid form with the N-bromo-succinimide, after ice-water bath is cooling, then add while stirring the mixed solution of the cooling methyl alcohol of ice-water bath, water, catalyzer; Perhaps first the N-bromo-succinimide is dissolved in the solution of methyl alcohol, water and catalyzer, then the limit stirring is added in the cooling N-of ice bath (2-carboxyl) phenylglycocoll or its chloro thing; Perhaps first N-(2-carboxyl) phenylglycocoll or its chloro thing and cold methanol, cold water mix are stirred, then add catalyzer, the cooling insulation of ice-water bath, more under agitation add once the N-bromo-succinimide; React 10 ~ 30min under the environment of 0 ~ 15 ℃, then go to and continue reaction under 20 ~ 30 ℃ of environment to the reaction end, obtain N-(4-bromo-3-chloro-2-carboxyl) phenylglycocoll or N-(the 4-bromo-2-carboxyl) phenylglycocoll shown in logical formula IV after purifying;
The consumption of described methyl alcohol is: 35～50ml/g N-(2-carboxyl) phenylglycocoll or its chloro thing, the consumption of described water is 10 ~ 47% of methanol usage volume, described catalyzer comprises hydrochloric acid, toluenesulphonic acids, sulfuric acid, ammonium nitrate, ammonium chloride, ammonium sulfate, with respect to N-(2-carboxyl) phenylglycocoll or its chloro thing, the consumption of hydrochloric acid, toluenesulphonic acids or sulfuric acid is all 2.9 ~ 8% molar equivalents, and the consumption of ammonium nitrate, ammonium chloride, ammonium sulfate is all 100 ~ 110% molar equivalents;
(c) N-(the 4-bromo-3-chloro-2-carboxyl) phenylglycocoll as shown in logical formula IV or N-(4-bromo-2-carboxyl) phenylglycocoll are obtained as leading to the 1-ethanoyl as shown in formula I-halogeno indole base-3-acetic ester through the Heumann reaction;
be specially: N-(4-bromo-3-chloro-2-carboxyl) phenylglycocoll or N-(4-bromo-2-carboxyl) phenylglycocoll and anhydrous sodium acetate are joined in the reaction flask that contains diacetyl oxide, the mass ratio of N-(4-bromo-3-chloro-2-carboxyl) phenylglycocoll or N-(4-bromo-2-carboxyl) phenylglycocoll and anhydrous sodium acetate is 1:1, the diacetyl oxide consumption is 10 ~ 20ml/g N-(4-bromo-3-chloro-2-carboxyl) phenylglycocoll or N-(4-bromo-2-carboxyl) phenylglycocoll, first oil bath is heated to 135～145 ℃ in advance, putting into reaction flask reacts keeping to bathe under temperature again, until till carbon dioxide no longer produces, reaction finishes, the ice-water bath product, after disappearing, oily liquids just can collect crude product, through washing, recrystallization namely obtains as leading to the 1-ethanoyl as shown in formula I-halogeno indole base-3-acetic ester,
R in above-mentioned formula I, (II), (III) and (IV)
1Represent Cl or H, R
2Represent H.
2. synthetic method according to claim 1, is characterized in that, utilize salt of wormwood or the sodium carbonate solution of described step (a) are controlled the pH value of reaction system 7.0～8.0.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2013100623544A CN103145605A (en) | 2013-02-27 | 2013-02-27 | Method for synthesizing 1-acetyl-halo-indolyl-3-acetate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2013100623544A CN103145605A (en) | 2013-02-27 | 2013-02-27 | Method for synthesizing 1-acetyl-halo-indolyl-3-acetate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103145605A true CN103145605A (en) | 2013-06-12 |
Family
ID=48543987
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2013100623544A Pending CN103145605A (en) | 2013-02-27 | 2013-02-27 | Method for synthesizing 1-acetyl-halo-indolyl-3-acetate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103145605A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106349306A (en) * | 2016-08-23 | 2017-01-25 | 广东优尼德生物科技有限公司 | Synthesis method of 5-bromo-4-chloro-3-indolyl-alpha-D-N-acetylneuraminic acid sodium salt |
| CN106986809A (en) * | 2016-12-02 | 2017-07-28 | 广东省微生物研究所（广东省微生物分析检测中心） | A kind of synthetic method of the indoles monooctyl ester of 5 bromine, 6 chlorine 3 |
| 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 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3509163A (en) * | 1967-01-25 | 1970-04-28 | Geigy Chem Corp | 2-alkanoyl or aroyl-3-aminoalkoxy indoles |
| CN101074229A (en) * | 2007-06-08 | 2007-11-21 | 无锡杰西医药科技有限公司 | 7-azaindirubin and 7-azaisoindigo derivative, its production and pharmaceutical use |
| WO2013010102A2 (en) * | 2011-07-14 | 2013-01-17 | Latham Keith R | Halogenated phenols for diagnostics, antioxidant protection and drug delivery |
-
2013
- 2013-02-27 CN CN2013100623544A patent/CN103145605A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3509163A (en) * | 1967-01-25 | 1970-04-28 | Geigy Chem Corp | 2-alkanoyl or aroyl-3-aminoalkoxy indoles |
| CN101074229A (en) * | 2007-06-08 | 2007-11-21 | 无锡杰西医药科技有限公司 | 7-azaindirubin and 7-azaisoindigo derivative, its production and pharmaceutical use |
| WO2013010102A2 (en) * | 2011-07-14 | 2013-01-17 | Latham Keith R | Halogenated phenols for diagnostics, antioxidant protection and drug delivery |
Non-Patent Citations (3)
| Title |
|---|
| GUYEN BERANGERE,等: "Synthesis and evaluation of analogs of 10H-indolo[3,2-b]quinoline as G-quadruplex stabilizing ligands and potential inhibitors of the enzyme telomerase", 《ORGANIC & BIOMOLECULAR CHEMISTRY》, vol. 2, no. 7, 10 March 2004 (2004-03-10), pages 981 - 988 * |
| RAMAKRISHNA V. S. NIROGI,等: "Indole-3-piperazinyl derivatives: Novel chemical class of 5-HT6 receptor antagonists", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》, vol. 21, no. 1, 5 November 2010 (2010-11-05), pages 346 - 349 * |
| ZHAO HUI WANG,等: "Synthesis and antitumor activity of 7-azaindirubin", 《CHINESE CHEMICAL LETTERS》, vol. 20, no. 5, 31 May 2009 (2009-05-31), pages 542 - 544 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106349306A (en) * | 2016-08-23 | 2017-01-25 | 广东优尼德生物科技有限公司 | Synthesis method of 5-bromo-4-chloro-3-indolyl-alpha-D-N-acetylneuraminic acid sodium salt |
| CN106986809A (en) * | 2016-12-02 | 2017-07-28 | 广东省微生物研究所（广东省微生物分析检测中心） | A kind of synthetic method of the indoles monooctyl ester of 5 bromine, 6 chlorine 3 |
| CN106986809B (en) * | 2016-12-02 | 2020-03-24 | 广东省微生物研究所（广东省微生物分析检测中心） | Synthesis method of 5-bromo-6-chloro-3-indoxyl |
| 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 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107935961A (en) | A kind of preparation method of 2 imino thiazole alkane, 4 ketone compounds | |
| CN103304512A (en) | Preparation method for febuxostat | |
| CN103145605A (en) | Method for synthesizing 1-acetyl-halo-indolyl-3-acetate | |
| CN106496038A (en) | A kind of preparation method of 3 methyl, 2 nitrobenzoic acid of high selectivity | |
| CN108191858B (en) | A kind of intermediate preparing pyrroloquinoline quinone and preparation method | |
| CN108358806B (en) | Continuous synthesis method of m-acetamidophenol | |
| CN102898328B (en) | Synthesis method of diethyl azodicarboxylate and intermediate of diethyl azodicarboxylate | |
| CN105384652B (en) | The method for preparing 2,5 2 (substitution) aryl amine terephthalic acids | |
| CN102911125B (en) | A kind of preparation method of Gefitinib intermediate | |
| CN103086903B (en) | The preparation method of a kind of glycine and ammonium chloride mixed crystal | |
| CN106986809A (en) | A kind of synthetic method of the indoles monooctyl ester of 5 bromine, 6 chlorine 3 | |
| CN104402795A (en) | Synthetic method of substituted indol-2-formic acid | |
| CN111303073B (en) | Method for preparing pesticide mefenacet by using benzothiazolone and 2-halogenated-N-methyl-N-phenyl acetamide | |
| CN100593540C (en) | Method for preparing 5-amido-1-(2,6-dichlorin-4-trifluoro methylbenzene)-3-cyano pyrazole | |
| CN106336352A (en) | Synthesis method of 6-fluorosalicylic acid | |
| CN105859559A (en) | Production method of 3-ethoxy-4-nitrophenol | |
| CN105837522A (en) | Preparation method of 1,5-benzodiazepine-one derivative | |
| Wang et al. | The Synthesis of 3, 4-Disubstituted Dihydroquinolin-2 (1 H)-One Under Metal-Free Conditions in Aqueous Solution | |
| CN101863836B (en) | Method for preparing 5,5-diphenyl-2-thiohydantoin | |
| CN105254614B (en) | A kind of synthetic method of ZD6474 compound | |
| CN104557604B (en) | Synthetic method for 5-acetylsalicylamide | |
| CN104327144B (en) | The preparation method of 3-hydroxyl-5-androstene-17 β carboxylate methyl ester | |
| WO2014146581A1 (en) | Method for preparing acrylate compound | |
| CN108587229B (en) | Preparation process and application of pyridone structure-containing disperse dye | |
| CN102010434A (en) | Preparation method for (7aR)-3-phenyl-6-benzyl-1H, 3H-imidazo [1,5-C] thiazole-(6H,7aH) 5,7-dione |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20130612 |