CN101585797A - 1-butyl-2,3,3-methyl-5-bromoindole iodide and preparation method thereof - Google Patents
1-butyl-2,3,3-methyl-5-bromoindole iodide and preparation method thereof Download PDFInfo
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Abstract
The invention relates to 1-butyl-2,3,3-methyl-5-bromoindole iodide and preparation method thereof, to solve the technical problems that the existing substance, 2,3,3-methyl-5-bromoindole has poor activity and complex transformation. The preparation of the novel substance, 1-butyl-2,3,3-methyl-5-bromoindole iodide, comprises the following three steps: preparation of p-bromophenylhydrazine hydrochloride, preparation of 2,3,3-trimethyl-5-bromoindole and final reaction. Because butyl and iodide ion are introduced, the activity of reaction is increased. Furthermore, the inventive 3-step process has high yield in the limited reaction condition and time.
Description
Technical field
The invention belongs to organic synthesis reagent and pharmaceutical intermediate field, relate to 1-butyl-2,3,3-methyl-5-bromo indole salt compounded of iodine and preparation method thereof.
Background of invention
Halogeno indole and derivative thereof are important organic synthesis reagent, are mainly used in Organic Chemicals and pharmacy field.Wherein 2,3,3-methyl-5-bromo indole a kind of especially important organic synthesis reagent and pharmaceutical intermediate are one of important source material of synthesizing antitumor, antiviral, anti-inflammatory, indoles medicine such as antibiotic.We introduce 2,3 with butyl and iodide ion, and 3-methyl-5-bromo indole has improved reactive behavior, has reduced the reaction requirement of subsequent reactions, has formed new organic compound 1-butyl-2,3,3-methyl-5-bromo indole salt compounded of iodine.In existing document, do not see relevant 1-butyl-2,3 as yet, 3-methyl-5-bromo indole salt compounded of iodine with and preparation method thereof report.
Summary of the invention
In order to solve 2,3,3-methyl-5-bromo indole is active not enough, conversion condition complicated technology problem, the invention provides 1-butyl-2,3,3-methyl-this novel cpd of 5-bromo indole salt compounded of iodine, the present invention provides 1-butyl-2,3 simultaneously, the preparation method of 3-methyl-5-bromo indole salt compounded of iodine.
The novel cpd 1-butyl-2,3 that the present invention relates to, 3-methyl-5-bromo indole salt compounded of iodine molecular structural formula is:
1-butyl-2,3, the preparation method of 3-methyl-5-bromo indole salt compounded of iodine is:
The first step is produced the para-bromophenyl-hydrazine hydrochloride: hydrochloric acid and para-bromoaniline are carried out reacting by heating, solution is cooled to-10～-5 ℃.Add NaNO then
2Solution carries out diazotization, and the reaction times is 30～60 minutes, and temperature of reaction is controlled at-10～-5 ℃.Add Na after the diazotization
2SO
3Solution reacts, and the reaction times is 1～3 hour, and temperature of reaction is controlled at 60～70 ℃.Add under the hydrochloric acid normal temperature reaction then, the reaction times is 1.5～2.5 hours, finishes after-filtration, with the salt acid elution repeatedly after, again with washing with alcohol to white.
In second step, produce 2,3,3-trimethylammonium-5-bromo indole: with para-bromophenyl-hydrazine, methyl isopropyl Ketone and ethanolic soln mixing stirring reaction, reaction times is 1～3 hour, is cooled to room temperature, adds strong sulfuric acid response then 2～4 hours, the reaction back adds extraction agent and extracts oil reservoir, washing, drying filters out to revolve behind the solid to steam and removes chloroform, product carries out column chromatography with eluent, obtains light yellow oily product.Wherein extraction agent can be chloroformic solution, and drying means can be for carrying out drying with anhydrous magnesium sulfate, and eluent can be methylene dichloride.
The 3rd step: produce 1-butyl-2,3,3-trimethylammonium-5-bromo indole salt compounded of iodine: with 2,3,3-trimethylammonium-5-bromo indole, butyl iodide and acetonitrile react, and wash after filtering out solid, washing methods can be colourless for washing to ethyl acetate with ethyl acetate, gets solid then after the drying.
Each the step reaction time in three reactions steps of experiment showed, is very big for the influence of yield and product purity, especially the reaction times in the 3rd step.Contrast by repetition test, find for 2,3 in the 3rd step, 3-trimethylammonium-5-bromo indole, butyl iodide and acetonitrile reacted 3～5 hours under the condition that the heating nothing refluxes earlier, be warming up to backflow after the end and reacted 12～18 hours again, its yield can reach more than 65%.Preferred embodiment is with 2,3, and 3-trimethylammonium-5-bromo indole, butyl iodide and acetonitrile reacted 4 hours under the condition that the heating nothing refluxes earlier, were warming up to backflow after the end and reacted 16 hours again, and yield can reach 73%.And, if the 3rd the step in 2,3,3-trimethylammonium-5-bromo indole, butyl iodide and acetonitrile direct heating are warming up to backflow, carry out back flow reaction, and be more simple to operate, but yield also reduces, and wherein reacts to be more excellent embodiment in 16～20 hours, and yield is about 60%.
Embodiment
The invention will be further described below with reference to embodiment, but therefore do not limit the present invention within the scope of embodiment.
Embodiment one:
The first step is produced the para-bromophenyl-hydrazine hydrochloride: the hydrochloric acid of 87.25mL is poured in the round-bottomed flask that fills the 20g para-bromoaniline heats, be cooled to-10～-5 ℃ then rapidly.Slowly add 8.26gNaNO
2Carry out diazotization with the mixing solutions of 30mL water.After dropwising, continue under-10～-5 ℃ temperature, to react 45 minutes, be poured into the Na of the new preparation that is cooled to 3 ℃ after reaction finishes
2SO
3In the saturated solution, after adding finishes temperature is elevated to 60～70 ℃ of following stirring reactions 2 hours, adds 100ml hydrochloric acid and reacted again 2 hours, the deep yellow solid is finished to filter out in the reaction back, with the salt acid elution repeatedly after, again with washing with alcohol to white, the oven dry weighing get solid 12g.
Second step, produce 2,3,3-trimethylammonium-5-bromo indole: with the para-bromophenyl-hydrazine of 20g, 15.39g methyl isopropyl Ketone and 51.3ml ethanol join in the there-necked flask of 250ml, churned mechanicallyly be heated to back flow reaction simultaneously 2 hours, be cooled to room temperature, the vitriol oil that dropwise adds 18.32ml, this moment, solution was blood red, was warming up to back flow reaction 3 hours after adding finishes, and after the cooling reaction solution was poured in the 200ml water, regulate pH value to 8, have oily matter to separate out this moment, adds the chloroform extraction oil-yielding stratum, washs three times, adding anhydrous magnesium sulfate drying spends the night, filter out to revolve behind the solid to steam and remove chloroform, product carries out column chromatography with methylene dichloride as eluent, obtains the light yellow oily product of 7.67g.
In the 3rd step, produce 1-butyl-2,3,3-trimethylammonium-5-bromo indole salt compounded of iodine: with 2 of 7.67g, 3, the butyl iodide of 3-trimethylammonium-5-bromo indole and 24.87g joins in the single port flask of 50ml, adds the acetonitrile of 20ml, reaction is 4 hours under the condition that the heating nothing refluxes, be warming up to back flow reaction after the end 16 hours, reaction is put into refrigerator overnight after finishing, and has red crystals to separate out, filter out wash to ethyl acetate with ethyl acetate behind the solid colourless, after the drying solid 10.13g.
Embodiment two:Be in, the reaction times difference of each step different with embodiment one.
The first step is produced the para-bromophenyl-hydrazine hydrochloride: the hydrochloric acid of 87.25mL is poured in the round-bottomed flask that fills the 20g para-bromoaniline heats, be cooled to-10～-5 ℃ then rapidly.Slowly add 8.26gNaNO
2Carry out diazotization with the mixing solutions of 30mL water.After dropwising, continuation was reacted 30 minutes under-10～-5 ℃ temperature, reaction is poured in the Na2SO3 saturated solution of the new preparation that is cooled to 3 ℃ after finishing, and after adding finishes temperature is elevated to 60～70 ℃ of following stirring reactions 1 hour, adds 100ml hydrochloric acid and reacts 1.5 hours again, the deep yellow solid is finished to filter out in the reaction back, with the salt acid elution repeatedly after, again with washing with alcohol to white, the oven dry weighing get solid 12g, yield 50%, fusing point＞250 ℃.
Second step, produce 2,3,3-trimethylammonium-5-bromo indole: with the para-bromophenyl-hydrazine of 20g, 15.39g methyl isopropyl Ketone and 51.3ml ethanol join in the there-necked flask of 250ml, churned mechanicallyly be heated to back flow reaction simultaneously 1 hour, be cooled to room temperature, the vitriol oil that dropwise adds 18.32ml, this moment, solution was blood red, was warming up to back flow reaction 2 hours after adding finishes, and after the cooling reaction solution was poured in the 200ml water, regulate pH value to 8, have oily matter to separate out this moment, adds the chloroform extraction oil-yielding stratum, washs three times, adding anhydrous magnesium sulfate drying spends the night, filter out to revolve behind the solid to steam and remove chloroform, product carries out column chromatography with methylene dichloride as eluent, obtains the light yellow oily product of 7.67g.
In the 3rd step, produce 1-butyl-2,3,3-trimethylammonium-5-bromo indole salt compounded of iodine: with 2 of 7.67g, 3, the butyl iodide of 3-trimethylammonium-5-bromo indole and 24.87g joins in the single port flask of 50ml, adds the acetonitrile of 20ml, reaction is 3 hours under the condition that the heating nothing refluxes, be warming up to back flow reaction after the end 12 hours, reaction is put into refrigerator overnight after finishing, and has red crystals to separate out, filter out wash to ethyl acetate with ethyl acetate behind the solid colourless, after the drying solid 10.13g.
Embodiment three:Be in, the reaction times difference of each step different with embodiment one.
The first step is produced the para-bromophenyl-hydrazine hydrochloride: the hydrochloric acid of 87.25mL is poured in the round-bottomed flask that fills the 20g para-bromoaniline heats, be cooled to-10～-5 ℃ then rapidly.Slowly add 8.26gNaNO
2Carry out diazotization with the mixing solutions of 30mL water.After dropwising, continuation was reacted 60 minutes under-10～-5 ℃ temperature, reaction is poured in the Na2SO3 saturated solution of the new preparation that is cooled to 3 ℃ after finishing, and after adding finishes temperature is elevated to 60～70 ℃ of following stirring reactions 3 hours, adds 100ml hydrochloric acid and reacts 2.5 hours again, the deep yellow solid is finished to filter out in the reaction back, with the salt acid elution repeatedly after, again with washing with alcohol to white, the oven dry weighing get solid 12g, yield 50%, fusing point＞250 ℃.
Second step, produce 2,3,3-trimethylammonium-5-bromo indole: with the para-bromophenyl-hydrazine of 20g, 15.39g methyl isopropyl Ketone and 51.3ml ethanol join in the there-necked flask of 250ml, churned mechanicallyly be heated to back flow reaction simultaneously 3 hours, be cooled to room temperature, the vitriol oil that dropwise adds 18.32ml, this moment, solution was blood red, was warming up to back flow reaction 4 hours after adding finishes, and after the cooling reaction solution was poured in the 200ml water, regulate pH value to 8, have oily matter to separate out this moment, adds the chloroform extraction oil-yielding stratum, washs three times, adding anhydrous magnesium sulfate drying spends the night, filter out to revolve behind the solid to steam and remove chloroform, product carries out column chromatography with methylene dichloride as eluent, obtains the light yellow oily product of 7.67g.
In the 3rd step, produce 1-butyl-2,3,3-trimethylammonium-5-bromo indole salt compounded of iodine: with 2 of 7.67g, 3, the butyl iodide of 3-trimethylammonium-5-bromo indole and 24.87g joins in the single port flask of 50ml, adds the acetonitrile of 20ml, reaction is 5 hours under the condition that the heating nothing refluxes, be warming up to back flow reaction after the end 18 hours, reaction is put into refrigerator overnight after finishing, and has red crystals to separate out, filter out wash to ethyl acetate with ethyl acetate behind the solid colourless, after the drying solid 10.13g.
Embodiment four:Be in, the reaction times difference of each step different with embodiment one.
The first step is produced the para-bromophenyl-hydrazine hydrochloride: the hydrochloric acid of 87.25mL is poured in the round-bottomed flask that fills the 20g para-bromoaniline heats, be cooled to-10～-5 ℃ then rapidly.Slowly add 8.26gNaNO
2Carry out diazotization with the mixing solutions of 30mL water.After dropwising, continuation was reacted 45 minutes under-10～-5 ℃ temperature, reaction is poured in the Na2SO3 saturated solution of the new preparation that is cooled to 3 ℃ after finishing, and after adding finishes temperature is elevated to 60～70 ℃ of following stirring reactions 2 hours, adds 100ml hydrochloric acid and reacts 2 hours again, the deep yellow solid is finished to filter out in the reaction back, with the salt acid elution repeatedly after, again with washing with alcohol to white, the oven dry weighing get solid 12g, yield 50%, fusing point＞250 ℃.
Second step, produce 2,3,3-trimethylammonium-5-bromo indole: with the para-bromophenyl-hydrazine of 20g, 15.39g methyl isopropyl Ketone and 51.3ml ethanol join in the there-necked flask of 250ml, churned mechanicallyly be heated to back flow reaction simultaneously 2 hours, be cooled to room temperature, the vitriol oil that dropwise adds 18.32ml, this moment, solution was blood red, was warming up to back flow reaction 3 hours after adding finishes, and after the cooling reaction solution was poured in the 200ml water, regulate pH value to 8, have oily matter to separate out this moment, adds the chloroform extraction oil-yielding stratum, washs three times, adding anhydrous magnesium sulfate drying spends the night, filter out to revolve behind the solid to steam and remove chloroform, product carries out column chromatography with methylene dichloride as eluent, obtains the light yellow oily product of 7.67g.
In the 3rd step, produce 1-butyl-2,3,3-trimethylammonium-5-bromo indole salt compounded of iodine: with 2 of 7.67g, 3, the butyl iodide of 3-trimethylammonium-5-bromo indole and 24.87g joins in the single port flask of 50ml, adds the acetonitrile of 20ml, reaction is 3 hours under the condition that the heating nothing refluxes, be warming up to back flow reaction after the end 12 hours, reaction is put into refrigerator overnight after finishing, and has red crystals to separate out, filter out wash to ethyl acetate with ethyl acetate behind the solid colourless, after the drying solid 10.13g.
Embodiment five:Be in, the reaction times difference of each step different with embodiment one.
The first step is produced the para-bromophenyl-hydrazine hydrochloride: the hydrochloric acid of 87.25mL is poured in the round-bottomed flask that fills the 20g para-bromoaniline heats, be cooled to-10～-5 ℃ then rapidly.Slowly add 8.26gNaNO
2Carry out diazotization with the mixing solutions of 30mL water.After dropwising, continuation was reacted 45 minutes under-10～-5 ℃ temperature, reaction is poured in the Na2SO3 saturated solution of the new preparation that is cooled to 3 ℃ after finishing, and after adding finishes temperature is elevated to 60～70 ℃ of following stirring reactions 2 hours, adds 100ml hydrochloric acid and reacts 2 hours again, the deep yellow solid is finished to filter out in the reaction back, with the salt acid elution repeatedly after, again with washing with alcohol to white, the oven dry weighing get solid 12g, yield 50%, fusing point＞250 ℃.
Second step, produce 2,3,3-trimethylammonium-5-bromo indole: with the para-bromophenyl-hydrazine of 20g, 15.39g methyl isopropyl Ketone and 51.3ml ethanol join in the there-necked flask of 250ml, churned mechanicallyly be heated to back flow reaction simultaneously 2 hours, be cooled to room temperature, the vitriol oil that dropwise adds 18.32ml, this moment, solution was blood red, was warming up to back flow reaction 3 hours after adding finishes, and after the cooling reaction solution was poured in the 200ml water, regulate pH value to 8, have oily matter to separate out this moment, adds the chloroform extraction oil-yielding stratum, washs three times, adding anhydrous magnesium sulfate drying spends the night, filter out to revolve behind the solid to steam and remove chloroform, product carries out column chromatography with methylene dichloride as eluent, obtains the light yellow oily product of 7.67g.
In the 3rd step, produce 1-butyl-2,3,3-trimethylammonium-5-bromo indole salt compounded of iodine: with 2 of 7.67g, 3, the butyl iodide of 3-trimethylammonium-5-bromo indole and 24.87g joins in the single port flask of 50ml, adds the acetonitrile of 20ml, reaction is 5 hours under the condition that the heating nothing refluxes, be warming up to back flow reaction after the end 18 hours, reaction is put into refrigerator overnight after finishing, and has red crystals to separate out, filter out wash to ethyl acetate with ethyl acetate behind the solid colourless, after the drying solid 10.13g.
Embodiment six:Be in, the reaction times difference of each step different with embodiment one.
The first step is produced the para-bromophenyl-hydrazine hydrochloride: the hydrochloric acid of 87.25mL is poured in the round-bottomed flask that fills the 20g para-bromoaniline heats, be cooled to-10～-5 ℃ then rapidly.Slowly add 8.26gNaNO
2Carry out diazotization with the mixing solutions of 30mL water.After dropwising, continuation was reacted 60 minutes under-10～-5 ℃ temperature, reaction is poured in the Na2SO3 saturated solution of the new preparation that is cooled to 3 ℃ after finishing, and after adding finishes temperature is elevated to 60～70 ℃ of following stirring reactions 3 hours, adds 100ml hydrochloric acid and reacts 2.5 hours again, the deep yellow solid is finished to filter out in the reaction back, with the salt acid elution repeatedly after, again with washing with alcohol to white, the oven dry weighing get solid 12g, yield 50%, fusing point＞250 ℃.
Second step, produce 2,3,3-trimethylammonium-5-bromo indole: with the para-bromophenyl-hydrazine of 20g, 15.39g methyl isopropyl Ketone and 51.3ml ethanol join in the there-necked flask of 250ml, churned mechanicallyly be heated to back flow reaction simultaneously 3 hours, be cooled to room temperature, the vitriol oil that dropwise adds 18.32ml, this moment, solution was blood red, was warming up to back flow reaction 4 hours after adding finishes, and after the cooling reaction solution was poured in the 200ml water, regulate pH value to 8, have oily matter to separate out this moment, adds the chloroform extraction oil-yielding stratum, washs three times, adding anhydrous magnesium sulfate drying spends the night, filter out to revolve behind the solid to steam and remove chloroform, product carries out column chromatography with methylene dichloride as eluent, obtains the light yellow oily product of 7.67g.
In the 3rd step, produce 1-butyl-2,3,3-trimethylammonium-5-bromo indole salt compounded of iodine: with 2 of 7.67g, 3, the butyl iodide of 3-trimethylammonium-5-bromo indole and 24.87g joins in the single port flask of 50ml, adds the acetonitrile of 20ml, reaction is 3 hours under the condition that the heating nothing refluxes, be warming up to back flow reaction after the end 12 hours, reaction is put into refrigerator overnight after finishing, and has red crystals to separate out, filter out wash to ethyl acetate with ethyl acetate behind the solid colourless, after the drying solid 10.13g.
Embodiment seven:Be in, the reaction times difference of each step different with embodiment one.
The first step is produced the para-bromophenyl-hydrazine hydrochloride: the hydrochloric acid of 87.25mL is poured in the round-bottomed flask that fills the 20g para-bromoaniline heats, be cooled to-10～-5 ℃ then rapidly.Slowly add 8.26gNaNO
2Carry out diazotization with the mixing solutions of 30mL water.After dropwising, continuation was reacted 30 minutes under-10～-5 ℃ temperature, reaction is poured in the Na2SO3 saturated solution of the new preparation that is cooled to 3 ℃ after finishing, and after adding finishes temperature is elevated to 60～70 ℃ of following stirring reactions 1 hour, adds 100ml hydrochloric acid and reacts 1.5 hours again, the deep yellow solid is finished to filter out in the reaction back, with the salt acid elution repeatedly after, again with washing with alcohol to white, the oven dry weighing get solid 12g, yield 50%, fusing point＞250 ℃.
Second step, produce 2,3,3-trimethylammonium-5-bromo indole: with the para-bromophenyl-hydrazine of 20g, 15.39g methyl isopropyl Ketone and 51.3ml ethanol join in the there-necked flask of 250ml, churned mechanicallyly be heated to back flow reaction simultaneously 1 hour, be cooled to room temperature, the vitriol oil that dropwise adds 18.32ml, this moment, solution was blood red, was warming up to back flow reaction 2 hours after adding finishes, and after the cooling reaction solution was poured in the 200ml water, regulate pH value to 8, have oily matter to separate out this moment, adds the chloroform extraction oil-yielding stratum, washs three times, adding anhydrous magnesium sulfate drying spends the night, filter out to revolve behind the solid to steam and remove chloroform, product carries out column chromatography with methylene dichloride as eluent, obtains the light yellow oily product of 7.67g.
In the 3rd step, produce 1-butyl-2,3,3-trimethylammonium-5-bromo indole salt compounded of iodine: with 2 of 7.67g, 3, the butyl iodide of 3-trimethylammonium-5-bromo indole and 24.87g joins in the single port flask of 50ml, adds the acetonitrile of 20ml, reaction is 5 hours under the condition that the heating nothing refluxes, be warming up to back flow reaction after the end 18 hours, reaction is put into refrigerator overnight after finishing, and has red crystals to separate out, filter out wash to ethyl acetate with ethyl acetate behind the solid colourless, after the drying solid 10.13g.
Embodiment eight:Be in, the reaction times difference of each step different with embodiment one, and in the 3rd step with 2,3,3-trimethylammonium-5-bromo indole, butyl iodide and acetonitrile direct heating are warming up to backflow, carry out back flow reaction.
The first step is produced the para-bromophenyl-hydrazine hydrochloride: the hydrochloric acid of 87.25mL is poured in the round-bottomed flask that fills the 20g para-bromoaniline heats, be cooled to-10～-5 ℃ then rapidly.Slowly add 8.26gNaNO
2Carry out diazotization with the mixing solutions of 30mL water.After dropwising, continuation was reacted 45 minutes under-10～-5 ℃ temperature, reaction is poured in the Na2SO3 saturated solution of the new preparation that is cooled to 3 ℃ after finishing, after adding finishes temperature is elevated to 60～70 ℃ of following stirring reactions 2 hours, add 100ml hydrochloric acid and reacted 2 hours again, the deep yellow solid is finished to filter out in the reaction back, with the salt acid elution repeatedly after, extremely white with washing with alcohol again, the oven dry weighing gets solid 12g.
Second step, produce 2,3,3-trimethylammonium-5-bromo indole: with the para-bromophenyl-hydrazine of 20g, 15.39g methyl isopropyl Ketone and 51.3ml ethanol join in the there-necked flask of 250ml, churned mechanicallyly be heated to back flow reaction simultaneously 2 hours, be cooled to room temperature, the vitriol oil that dropwise adds 18.32ml, this moment, solution was blood red, was warming up to back flow reaction 3 hours after adding finishes, and after the cooling reaction solution was poured in the 200ml water, regulate pH value to 8, have oily matter to separate out this moment, adds the chloroform extraction oil-yielding stratum, washs three times, adding anhydrous magnesium sulfate drying spends the night, filter out to revolve behind the solid to steam and remove chloroform, product carries out column chromatography with methylene dichloride as eluent, obtains the light yellow oily product of 7.67g.
The 3rd step, produce 1-butyl-2,3,3-trimethylammonium-5-bromo indole salt compounded of iodine: with 2 of 7.67g, 3, the butyl iodide of 3-trimethylammonium-5-bromo indole and 24.87g joins in the single port flask of 50ml, adds the acetonitrile of 20ml, and heat temperature raising was to back flow reaction 16 hours, reaction is put into refrigerator overnight after finishing, have red crystals to separate out, filter out wash to ethyl acetate with ethyl acetate behind the solid colourless, after the drying solid 10.13g.
Embodiment nine:Be in, the reaction times difference of each step different with embodiment one, and in the 3rd step with 2,3,3-trimethylammonium-5-bromo indole, butyl iodide and acetonitrile direct heating are warming up to backflow, carry out back flow reaction.
The first step is produced the para-bromophenyl-hydrazine hydrochloride: the hydrochloric acid of 87.25mL is poured in the round-bottomed flask that fills the 20g para-bromoaniline heats, be cooled to-10～-5 ℃ then rapidly.Slowly add 8.26gNaNO
2Carry out diazotization with the mixing solutions of 30mL water.After dropwising, continuation was reacted 30 minutes under-10～-5 ℃ temperature, reaction is poured in the Na2SO3 saturated solution of the new preparation that is cooled to 3 ℃ after finishing, and after adding finishes temperature is elevated to 60～70 ℃ of following stirring reactions 1 hour, adds 100ml hydrochloric acid and reacts 1.5 hours again, the deep yellow solid is finished to filter out in the reaction back, with the salt acid elution repeatedly after, again with washing with alcohol to white, the oven dry weighing get solid 12g, yield 50%, fusing point＞250 ℃.
Second step, produce 2,3,3-trimethylammonium-5-bromo indole: with the para-bromophenyl-hydrazine of 20g, 15.39g methyl isopropyl Ketone and 51.3ml ethanol join in the there-necked flask of 250ml, churned mechanicallyly be heated to back flow reaction simultaneously 1 hour, be cooled to room temperature, the vitriol oil that dropwise adds 18.32ml, this moment, solution was blood red, was warming up to back flow reaction 2 hours after adding finishes, and after the cooling reaction solution was poured in the 200ml water, regulate pH value to 8, have oily matter to separate out this moment, adds the chloroform extraction oil-yielding stratum, washs three times, adding anhydrous magnesium sulfate drying spends the night, filter out to revolve behind the solid to steam and remove chloroform, product carries out column chromatography with methylene dichloride as eluent, obtains the light yellow oily product of 7.67g.
The 3rd step, produce 1-butyl-2,3,3-trimethylammonium-5-bromo indole salt compounded of iodine: with 2 of 7.67g, 3, the butyl iodide of 3-trimethylammonium-5-bromo indole and 24.87g joins in the single port flask of 50ml, adds the acetonitrile of 20ml, and heat temperature raising was to back flow reaction 16 hours, reaction is put into refrigerator overnight after finishing, have red crystals to separate out, filter out wash to ethyl acetate with ethyl acetate behind the solid colourless, after the drying solid 10.13g.
Embodiment ten:Be in, the reaction times difference of each step different with embodiment one, and in the 3rd step with 2,3,3-trimethylammonium-5-bromo indole, butyl iodide and acetonitrile direct heating are warming up to backflow, carry out back flow reaction.
The first step is produced the para-bromophenyl-hydrazine hydrochloride: the hydrochloric acid of 87.25mL is poured in the round-bottomed flask that fills the 20g para-bromoaniline heats, be cooled to-10～-5 ℃ then rapidly.Slowly add 8.26gNaNO
2Carry out diazotization with the mixing solutions of 30mL water.After dropwising, continuation was reacted 60 minutes under-10～-5 ℃ temperature, reaction is poured in the Na2SO3 saturated solution of the new preparation that is cooled to 3 ℃ after finishing, and after adding finishes temperature is elevated to 60～70 ℃ of following stirring reactions 3 hours, adds 100ml hydrochloric acid and reacts 2.5 hours again, the deep yellow solid is finished to filter out in the reaction back, with the salt acid elution repeatedly after, again with washing with alcohol to white, the oven dry weighing get solid 12g, yield 50%, fusing point＞250 ℃.
Second step, produce 2,3,3-trimethylammonium-5-bromo indole: with the para-bromophenyl-hydrazine of 20g, 15.39g methyl isopropyl Ketone and 51.3ml ethanol join in the there-necked flask of 250ml, churned mechanicallyly be heated to back flow reaction simultaneously 3 hours, be cooled to room temperature, the vitriol oil that dropwise adds 18.32ml, this moment, solution was blood red, was warming up to back flow reaction 4 hours after adding finishes, and after the cooling reaction solution was poured in the 200ml water, regulate pH value to 8, have oily matter to separate out this moment, adds the chloroform extraction oil-yielding stratum, washs three times, adding anhydrous magnesium sulfate drying spends the night, filter out to revolve behind the solid to steam and remove chloroform, product carries out column chromatography with methylene dichloride as eluent, obtains the light yellow oily product of 7.67g.
In the 3rd step, produce 1-butyl-2,3,3-trimethylammonium-5-bromo indole salt compounded of iodine: with 2 of 7.67g, 3, the butyl iodide of 3-trimethylammonium-5-bromo indole and 24.87g joins in the single port flask of 50ml, adds the acetonitrile of 20ml, reaction is 5 hours under the condition that the heating nothing refluxes, be warming up to back flow reaction after the end 18 hours, reaction is put into refrigerator overnight after finishing, and has red crystals to separate out, filter out wash to ethyl acetate with ethyl acetate behind the solid colourless, after the drying solid 10.13g.
Embodiment 11:Be in, the reaction times difference of each step different with embodiment one, and in the 3rd step with 2,3,3-trimethylammonium-5-bromo indole, butyl iodide and acetonitrile direct heating are warming up to backflow, carry out back flow reaction.
The first step is produced the para-bromophenyl-hydrazine hydrochloride: the hydrochloric acid of 87.25mL is poured in the round-bottomed flask that fills the 20g para-bromoaniline heats, be cooled to-10～-5 ℃ then rapidly.Slowly add 8.26gNaNO
2Carry out diazotization with the mixing solutions of 30mL water.After dropwising, continuation was reacted 45 minutes under-10～-5 ℃ temperature, reaction is poured in the Na2SO3 saturated solution of the new preparation that is cooled to 3 ℃ after finishing, and after adding finishes temperature is elevated to 60～70 ℃ of following stirring reactions 2 hours, adds 100ml hydrochloric acid and reacts 2 hours again, the deep yellow solid is finished to filter out in the reaction back, with the salt acid elution repeatedly after, again with washing with alcohol to white, the oven dry weighing get solid 12g, yield 50%, fusing point＞250 ℃.
Second step, produce 2,3,3-trimethylammonium-5-bromo indole: with the para-bromophenyl-hydrazine of 20g, 15.39g methyl isopropyl Ketone and 51.3ml ethanol join in the there-necked flask of 250ml, churned mechanicallyly be heated to back flow reaction simultaneously 2 hours, be cooled to room temperature, the vitriol oil that dropwise adds 18.32ml, this moment, solution was blood red, was warming up to back flow reaction 3 hours after adding finishes, and after the cooling reaction solution was poured in the 200ml water, regulate pH value to 8, have oily matter to separate out this moment, adds the chloroform extraction oil-yielding stratum, washs three times, adding anhydrous magnesium sulfate drying spends the night, filter out to revolve behind the solid to steam and remove chloroform, product carries out column chromatography with methylene dichloride as eluent, obtains the light yellow oily product of 7.67g.
The 3rd step, produce 1-butyl-2,3,3-trimethylammonium-5-bromo indole salt compounded of iodine: with 2 of 7.67g, 3, the butyl iodide of 3-trimethylammonium-5-bromo indole and 24.87g joins in the single port flask of 50ml, adds the acetonitrile of 20ml, and heat temperature raising was to back flow reaction 20 hours, reaction is put into refrigerator overnight after finishing, have red crystals to separate out, filter out wash to ethyl acetate with ethyl acetate behind the solid colourless, after the drying solid 10.13g.
Embodiment 12:Be in, the reaction times difference of each step different with embodiment one, and in the 3rd step with 2,3,3-trimethylammonium-5-bromo indole, butyl iodide and acetonitrile direct heating are warming up to backflow, carry out back flow reaction.
The first step is produced the para-bromophenyl-hydrazine hydrochloride: the hydrochloric acid of 87.25mL is poured in the round-bottomed flask that fills the 20g para-bromoaniline heats, be cooled to-10～-5 ℃ then rapidly.Slowly add 8.26gNaNO
2Carry out diazotization with the mixing solutions of 30mL water.After dropwising, continuation was reacted 45 minutes under-10～-5 ℃ temperature, reaction is poured in the Na2SO3 saturated solution of the new preparation that is cooled to 3 ℃ after finishing, and after adding finishes temperature is elevated to 60～70 ℃ of following stirring reactions 2 hours, adds 100ml hydrochloric acid and reacts 2 hours again, the deep yellow solid is finished to filter out in the reaction back, with the salt acid elution repeatedly after, again with washing with alcohol to white, the oven dry weighing get solid 12g, yield 50%, fusing point＞250 ℃.
Second step, produce 2,3,3-trimethylammonium-5-bromo indole: with the para-bromophenyl-hydrazine of 20g, 15.39g methyl isopropyl Ketone and 51.3ml ethanol join in the there-necked flask of 250ml, churned mechanicallyly be heated to back flow reaction simultaneously 2 hours, be cooled to room temperature, the vitriol oil that dropwise adds 18.32ml, this moment, solution was blood red, was warming up to back flow reaction 3 hours after adding finishes, and after the cooling reaction solution was poured in the 200ml water, regulate pH value to 8, have oily matter to separate out this moment, adds the chloroform extraction oil-yielding stratum, washs three times, adding anhydrous magnesium sulfate drying spends the night, filter out to revolve behind the solid to steam and remove chloroform, product carries out column chromatography with methylene dichloride as eluent, obtains the light yellow oily product of 7.67g.
In the 3rd step, produce 1-butyl-2,3,3-trimethylammonium-5-bromo indole salt compounded of iodine: with 2 of 7.67g, 3, the butyl iodide of 3-trimethylammonium-5-bromo indole and 24.87g joins in the single port flask of 50ml, adds the acetonitrile of 20ml, reaction is 5 hours under the condition that the heating nothing refluxes, be warming up to back flow reaction after the end 18 hours, reaction is put into refrigerator overnight after finishing, and has red crystals to separate out, filter out wash to ethyl acetate with ethyl acetate behind the solid colourless, after the drying solid 10.13g.
Embodiment 13:Be in, the reaction times difference of each step different with embodiment one, and in the 3rd step with 2,3,3-trimethylammonium-5-bromo indole, butyl iodide and acetonitrile direct heating are warming up to backflow, carry out back flow reaction.
The first step is produced the para-bromophenyl-hydrazine hydrochloride: the hydrochloric acid of 87.25mL is poured in the round-bottomed flask that fills the 20g para-bromoaniline heats, be cooled to-10～-5 ℃ then rapidly.Slowly add 8.26gNaNO
2Carry out diazotization with the mixing solutions of 30mL water.After dropwising, continuation was reacted 60 minutes under-10～-5 ℃ temperature, reaction is poured in the Na2SO3 saturated solution of the new preparation that is cooled to 3 ℃ after finishing, and after adding finishes temperature is elevated to 60～70 ℃ of following stirring reactions 3 hours, adds 100ml hydrochloric acid and reacts 2.5 hours again, the deep yellow solid is finished to filter out in the reaction back, with the salt acid elution repeatedly after, again with washing with alcohol to white, the oven dry weighing get solid 12g, yield 50%, fusing point＞250 ℃.
Second step, produce 2,3,3-trimethylammonium-5-bromo indole: with the para-bromophenyl-hydrazine of 20g, 15.39g methyl isopropyl Ketone and 51.3ml ethanol join in the there-necked flask of 250ml, churned mechanicallyly be heated to back flow reaction simultaneously 3 hours, be cooled to room temperature, the vitriol oil that dropwise adds 18.32ml, this moment, solution was blood red, was warming up to back flow reaction 4 hours after adding finishes, and after the cooling reaction solution was poured in the 200ml water, regulate pH value to 8, have oily matter to separate out this moment, adds the chloroform extraction oil-yielding stratum, washs three times, adding anhydrous magnesium sulfate drying spends the night, filter out to revolve behind the solid to steam and remove chloroform, product carries out column chromatography with methylene dichloride as eluent, obtains the light yellow oily product of 7.67g.
In the 3rd step, produce 1-butyl-2,3,3-trimethylammonium-5-bromo indole salt compounded of iodine: with 2 of 7.67g, 3, the butyl iodide of 3-trimethylammonium-5-bromo indole and 24.87g joins in the single port flask of 50ml, adds the acetonitrile of 20ml, reaction is 3 hours under the condition that the heating nothing refluxes, be warming up to back flow reaction after the end 12 hours, reaction is put into refrigerator overnight after finishing, and has red crystals to separate out, filter out wash to ethyl acetate with ethyl acetate behind the solid colourless, after the drying solid 10.13g.
Claims (9)
1,1-butyl-2,3,3-methyl-5-bromo indole salt compounded of iodine, its structural formula is
2,1-butyl-2,3, the preparation method of 3-methyl-5-bromo indole salt compounded of iodine:
The first step is produced the para-bromophenyl-hydrazine hydrochloride: hydrochloric acid and para-bromoaniline are carried out reacting by heating, add NaNO then
2Solution carries out diazotization.Add Na after the diazotization
2SO
3Solution reaction adds hydrochloric acid reaction again, and reaction finishes after-filtration, with the salt acid elution repeatedly after, again with washing with alcohol to white;
Second step, produce 2,3,3-trimethylammonium-5-bromo indole:, add the vitriol oil then and react with para-bromophenyl-hydrazine, methyl isopropyl Ketone and ethanolic soln hybrid reaction, oily matter to be had is separated out, add extraction agent and extract the oil reservoir after scouring, drying filters out to revolve to steam behind the solid and removes chloroform, product carries out column chromatography with eluent, obtains light yellow oily product;
In the 3rd step, produce 1-butyl-2,3,3-trimethylammonium-5-bromo indole salt compounded of iodine: with 2,3,3-trimethylammonium-5-bromo indole, butyl iodide and acetonitrile react, and wash drying after filtering out solid.
3, preparation 1-butyl-2,3 according to claim 2, the method for 3-methyl-5-bromo indole salt compounded of iodine is characterized in that: after hydrochloric acid and para-bromoaniline carry out reacting by heating in the described the first step, solution is cooled to-10～-5 ℃; Diazotizing temperature of reaction is controlled at-10～-5 ℃; Add Na
2SO
3The temperature of reaction of reaction is controlled at 60～70 ℃.
4, according to claim 2 or 3 described preparation 1-butyl-2,3, the method of 3-methyl-5-bromo indole salt compounded of iodine, it is characterized in that: the diazotizing reaction times is 30～60 minutes in the described the first step, the time that adding Na2SO3 solution reacts after the diazotization is 1～3 hour, and the time that adding hydrochloric acid reacts again is 1.5～2.5 hours.
5, according to claim 2 or 3 described preparation 1-butyl-2,3, the method of 3-methyl-5-bromo indole salt compounded of iodine, it is characterized in that: in described second step para-bromophenyl-hydrazine hydrochloride, methyl isopropyl Ketone and ethanol being mixed the time of carrying out stirring reaction is 1～3 hour, and the time that adds strong sulfuric acid response is 2～4 hours.
6. according to claim 2 or 3 described preparation 1-butyl-2,3, the method of 3-methyl-5-bromo indole salt compounded of iodine, it is characterized in that: the extraction agent in described second step is a chloroformic solution, drying means in described second step is for to carry out drying with anhydrous magnesium sulfate as siccative, and the eluent in described second step is a methylene dichloride.
7. preparation 1-butyl-2 according to claim 6,3, the method of 3-methyl-5-bromo indole salt compounded of iodine, it is characterized in that: described the 3rd the step in 2,3, the process that 3-trimethylammonium-5-bromo indole, butyl iodide and acetonitrile react is that elder generation carried out 3～5 hours under the condition that the heating nothing refluxes, and was warming up to backflow then and reacted 12～16 hours again.
8. preparation 1-butyl-2 according to claim 2,3, the method of 3-methyl-5-bromo indole salt compounded of iodine, it is characterized in that: described the 3rd the step in 2,3, the process that 3-trimethylammonium-5-bromo indole, butyl iodide and acetonitrile react is, heat temperature raising is to refluxing, and the time of back flow reaction is 16～20 hours.
9. preparation 1-butyl-2,3 according to claim 2, the method for 3-methyl-5-bromo indole salt compounded of iodine is characterized in that: the washing methods in described the 3rd step is for to wash to ethyl acetate colourless with ethyl acetate.
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