CN104193616B - The synthetic method of the chloro-5-iodo-benzoic acid of a kind of 2- - Google Patents
The synthetic method of the chloro-5-iodo-benzoic acid of a kind of 2- Download PDFInfo
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- CN104193616B CN104193616B CN201410214642.1A CN201410214642A CN104193616B CN 104193616 B CN104193616 B CN 104193616B CN 201410214642 A CN201410214642 A CN 201410214642A CN 104193616 B CN104193616 B CN 104193616B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
Abstract
The synthetic method disclosing the chloro-5-iodo-benzoic acid of a kind of 2-of the present invention, by methyl o-aminobenzoate through iodo, replacement, sandmeyer reaction, then obtain target product in the Water Under solution of alkali, its innovative point is: obtain on mayer reaction and hydrolysis reaction by the improvement of processing step and parameter or optimization in traditional iodo, substitution reaction, mulberry.Method technique of the present invention is more simple, and easy to operate, production process safety, pollution-free, the yield of separate operations is higher, and product purity is up to 95 ~ 98%, and total yield of products is up to 64 ~ 70%.
Description
Technical field
The present invention relates to a kind of phenylformic acid synthetic method, particularly relate to the synthetic method of the chloro-5-iodo-benzoic acid of a kind of 2-, belong to the field of chemical synthesis.
Background technology
2-chloro-5-iodo-benzoic acid is the aromaticity function monomer with two kinds of different halogens and a carboxyl, the activity difference of each group can be utilized, from different radical reaction, synthesize the compound that multiple functional group replaces, be widely used in medicine, Organometallic Chemistry etc., be mainly used in the synthesis of up-to-date ofhypoglycemic medicine dapagliflozin (BMS-512148).About its synthetic method, current bibliographical information is less.
Disclose at present a kind of with the methyl o-aminobenzoate of cheapness for starting raw material, carry out iodide reaction with iodine and obtain 2-amino-5 iodo-benzoic acid methyl esters, then classical sandmeyer reaction is carried out, the chloro-5 iodo-benzoic acid methyl esters of 2-are obtained after chloro, finally be hydrolyzed to obtain chloro-5 iodo-benzoic acids of target product 2-, total recovery only has about 50.2%.It is low to there is yield in this synthetic method, and synthetic method is complicated, and the shortcomings such as troublesome poeration, have much room for improvement.
Summary of the invention
The object of the invention is to solve defect of the prior art, provide a kind of technique simple, easy to operate, be applicable to the synthesis production method of the chloro-5-iodo-benzoic acid of a kind of 2-of suitability for industrialized production.
In order to solve the problems of the technologies described above, the solution that the present invention adopts is: the synthetic method of the chloro-5-iodo-benzoic acid of a kind of 2-, comprise iodo, substitution reaction, mulberry obtains mayer reaction and hydrolysis reaction, its innovative point is: described iodo, substitution reaction is for determining that raw material and the reagent mass ratio that feeds intake is methyl o-aminobenzoate: Potassium Iodate: iodinating agent: methylene dichloride: water: S-WAT: ethanol: methanol solution of sodium methylate: acetic acid: water=1:0.4 ~ 0.5::0.8 ~ 1:2 ~ 5:1.5 ~ 3::0.008 ~ 0.01:3 ~ 5:0.25 ~ 0.4:0.02 ~ 0.05:0.08 ~ 0.1, water is added in proportion in reaction flask, iodinating agent stirring and dissolving, to add after Potassium Iodate stirring and dissolving again, then methyl o-aminobenzoate and solvent is added successively, drip glacial acetic acid, controlling dropping temperature is 50 ~ 55 DEG C, add rear stirring 30 ~ 120 minutes, heat temperature raising, temperature is raised to and is incubated after 55 ~ 80 DEG C, arranging soaking time is 2 ~ 3h,
Cool after insulation terminates, after being cooled to 30 ~ 35 DEG C, adding solid sodium sulfite after stirring 15 ~ 30min in proportion and carry out except look, continue to be cooled to 20 ~ 25 DEG C, stratification, is divided into water layer and oil reservoir, adds in proportion after methylene dichloride carries out reextraction and collects oil reservoir;
Merge once, secondary oil reservoir, merging oil reservoir is passed through air distillation, controlling distillation temperature is 35 ~ 60 DEG C, the temperature cooling leftover materials after normal pressure removing cut is 30 ~ 35 DEG C, after adding ethanol stirring and dissolving leftover materials, add sodium methylate and be heated to backflow, insulation 1 ~ 2h, controlling distillation temperature is 82 ~ 83 DEG C, normal pressure boils off the mixture of methyl alcohol and ethanol, slowly acetic acid is dripped by proportioning in residuum, add the water of dosage again, be cooled to 0 ~ 5 DEG C of filtration, filtration gained solid drying under reduced pressure carries out oven dry and obtains 2-amino-5-iodo ethyl benzoate, control the temperature < 30 DEG C of drying under reduced pressure, the pressure of drying under reduced pressure is-0.085MPa, time 6 ~ the 8h of drying under reduced pressure,
Reaction formula is:
Described mulberry obtains mayer reaction for determining that raw material and the reagent mass ratio that feeds intake is 2-amino-5-iodo ethyl benzoate: diazonium salt water: diazonium salt hydrochloric acid: Sodium Nitrite: join sodium salt water: replacement water: replacement hydrochloric acid: cuprous chloride: methylene dichloride: saturated aqueous common salt: bath water: anhydrous sodium sulphate=1:1 ~ 2:2.2 ~ 2.5:0.25 ~ 0.3:0.4 ~ 1:0.4 ~ 1:2 ~ 3:0.1 ~ 0.3:2.5 ~ 4:2 ~ 4:1 ~ 3::0.1 ~ 0.3, water is added in proportion in the first reaction flask, hydrochloric acid stirring and dissolving, divide 3 ~ 6 batches, add 2-amino-5-iodo ethyl benzoate at every turn, control temperature is 20 ~ 25 DEG C and stirs 0.5 ~ 2h, drip sodium nitrite in aqueous solution after temperature being cooled to 0 ~ 5 DEG C and carry out diazotization reaction, the time arranging diazotization reaction is 0.5 ~ 3h, temperature of reaction is < 5 DEG C, reaction terminates rear stirring 0.5 ~ 3h,
In the second reaction flask, add water by proportioning, hydrochloric acid set temperature be at 25 ~ 30 DEG C stir add cuprous chloride, then the diazo liquid that diazotization obtains is added dropwise in reaction soln, dropping terminates rear stirring 1 ~ 2 hour, > 24h is stirred after being heated to 35 DEG C subsequently, when controlling to stir, temperature is 30 ~ 35 DEG C, add methylene dichloride by proportioning to stir 15 ~ 45 minutes, stratification, washes twice altogether.Merge once, after secondary oil reservoir, with diatomite filtration filtering mantoquita, after filtering, filtrate adds saturated common salt water washing standing twice by proportioning, each washing leaves standstill after 15 ~ 45 minutes and is divided into water layer and oil reservoir in 15-30 minute, water washing stratification is added by proportioning with layer, stir 15 ~ 30 minutes, leave standstill 15 ~ 30 minutes, merge oil reservoir, anhydrous sodium sulphate drying is added by proportioning, filter, underpressure distillation boils off solvent, the time arranging underpressure distillation is 0.5 ~ 2.5h, the pressure of underpressure distillation is >-0.085MPa, the temperature of underpressure distillation is < 20 DEG C, finally obtain the chloro-5-iodo ethyl benzoate of product 2-.
Reaction formula is:
Described hydrolysis reaction is for determining that raw material and the reagent mass ratio that feeds intake is the chloro-5-iodo ethyl benzoate of 2-: water: sodium hydroxide: ethanol: hydrochloric acid: 1% hydrochloric acid=1:4 ~ 6:0.1 ~ 0.3:0.1 ~ 0.5:0.5 ~ 2:5 ~ 8.
First in reaction flask, add water, sodium hydroxide and ethanol heat temperature raising while stirring, be heated to 75 ~ 80 DEG C, control temperature drips the chloro-5-iodo ethyl benzoate of 2-and reacts at 75 ~ 80 DEG C, diatomite filtration is passed through after reacting completely, the filtrate filtered out under agitation adds hydrochloric acid by proportioning, regulate filtrate PH=1 ~ 2, filter after continuing stirring 0.5 ~ 1h, 1% hydrochloric acid stirring to pulp of filter cake dosage 2 ~ 3 times, each making beating 30 ~ 35 minutes, again filter, filtration gained solid drying under reduced pressure carries out oven dry and obtains the chloro-5-iodo-benzoic acid of 2-, the temperature controlling drying under reduced pressure is < 50 DEG C, the pressure of drying under reduced pressure is >-0.085MPa, the time of drying under reduced pressure is 6 ~ 8h.
Reaction formula is:
Further, the iodinating agent in described iodo, substitution reaction is iodine or salt compounded of iodine.
Further, the solvent in described iodo, substitution reaction and the reaction of Sang get mayer is methylene dichloride, tetrahydrofuran (THF) or DMF.
Further, the methyl o-aminobenzoate in described iodo, substitution reaction and the mass ratio of iodo agent are 1:0.8 ~ 1.2.
Further, chloro-for 2-5-iodo-benzoic acid sodium is replaced as the chloro-5-iodo-benzoic acid of 2-by strong acid solution adjust ph by the filtrate after described hydrolysis reaction, and wherein pH value is 1 ~ 2.
Further, in described iodo, substitution reaction, the density of sodium methylate is 27.6 ~ 30%.
Beneficial effect: the synthetic method of the chloro-5-iodo-benzoic acid of this 2-of the present invention, the improvement by processing step and parameter on mayer reaction and hydrolysis reaction is obtained in traditional iodo, substitution reaction, mulberry, technique is simpler, easy to operate, production process safety, pollution-free, the yield of separate operations all reaches higher level, product purity is up to 95 ~ 98%, and total yield of products is up to 64 ~ 70%.
Embodiment
Implementation column below can make those skilled in the art more fully understand the present invention, but does not therefore limit the present invention among described scope of embodiments.
embodiment 1
The synthetic method of the chloro-5-iodo-benzoic acid of a kind of 2-:
1, iodo, replacement
Determine that raw material and the reagent mass ratio that feeds intake is methyl o-aminobenzoate: Potassium Iodate: iodinating agent: methylene dichloride: water: S-WAT: ethanol: methanol solution of sodium methylate: acetic acid: water=1:0.4 ~ 0.5:0.8 ~ 1:2 ~ 5:1.5 ~ 3:0.008 ~ 0.01:3 ~ 5:0.25 ~ 0.4:0.02 ~ 0.05:0.08 ~ 0.1
The potassiumiodide stirring and dissolving of the water of 588ml, 242.4g is added in 2L there-necked flask.Add the Potassium Iodate of 139.1g, stirring and dissolving, add 300g methyl o-aminobenzoate, add 99.3ml methylene dichloride again, dripped the glacial acetic acid of 191.8g by addition funnel, 1.5 hours add, and temperature is raised to 50 DEG C, add rear stirring 30 minutes, temperature is raised to 55 DEG C of insulations 2 hours, is cooled to 35 DEG C, adds the methylene dichloride of 397.4ml, stir and add 2.8g solid sodium sulfite after 15 minutes in batches, be cooled to 25 DEG C, stratification, collect oil reservoir, water layer 100ml dichloromethane extraction, merges oil reservoir.Oil reservoir air distillation temperature is steamed to 82 DEG C, cooling leftover materials are to 50 DEG C, add 1050.2g ethanol, stirring and dissolving leftover materials add 86.2g(27.6%) sodium methoxide solution be heated to flow, be incubated 1 hour, normal pressure boils off the mixture of methyl alcohol and ethanol, temperature is no more than 83 DEG C and steams solvent, in residuum, slowly drip 7.6g acetic acid add 25.8g water again, be cooled to 0 ~ 5 DEG C of filtration, filter out < 30 DEG C of decompression dryings after solid, control vacuum tightness >-0.085MPa, the time of drying under reduced pressure is (6 ~ 10h), obtain product 463.3g, product yield 80.2%.
2, mulberry obtains mayer reaction
Determine that raw material and the reagent mass ratio that feeds intake is 2-amino-5-iodo ethyl benzoate: diazonium salt water: diazonium salt hydrochloric acid: Sodium Nitrite: join sodium salt water: replacement water: replacement hydrochloric acid: cuprous chloride: methylene dichloride: saturated aqueous common salt: bath water: anhydrous sodium sulphate=1:1 ~ 2:2.2 ~ 2.5:0.25 ~ 0.3:0.4 ~ 1:0.4 ~ 1:2 ~ 3:0.1 ~ 0.3:2.5 ~ 4:2 ~ 4:1 ~ 3::0.1 ~ 0.3 adds the water of 264ml in 2L there-necked flask, 467g hydrochloric acid stirs, add the 2-amino-5-iodo ethyl benzoate temperature that total amount is 193g, control temperature 20 ~ 25 DEG C stirring (0.5 ~ 2h).Temperature is cooled to 5 DEG C, and the water stirring and dissolving of 51g Sodium Nitrite and 93ml is stand-by, and control temperature 0 ~ 5 DEG C drips sodium nitrite solution and carries out diazotization reaction, terminates rear stirring 15 minutes.In 2L there-necked flask, add 93ml water, 467g hydrochloric acid adds 26g cuprous chloride control temperature 25-30 DEG C under stirring, diazo liquid is added dropwise in reaction solution, drip and terminate rear stirring 1 ~ 2 hour, be heated to 35 DEG C and stir 24h, control temperature 30 ~ 35 DEG C.Wash at twice with the methylene dichloride of 530g, wash 30min at every turn, leave standstill 15min.Merge oil reservoir, leach mantoquita with diatomite filtration.Filtrate washs 30min at twice with saturated aqueous common salt 400ml, leave standstill 15min layering, oil reservoir adds 273ml water and stirs washing layering in 15 minutes, and oil reservoir adds 20g anhydrous sodium sulphate drying, filters, pressure reducing and steaming methylene dichloride, arrange the time of underpressure distillation for (0.5 ~ 2.5h), the pressure of underpressure distillation is (-0.085MPa), and the temperature of underpressure distillation is < 20 DEG C, obtain product 2-chloro-5-iodo ethyl benzoate 178.7g, product yield is 86.8%.
3, hydrolysis reaction
Determine that raw material and the reagent mass ratio that feeds intake is the chloro-5-iodo ethyl benzoate of 2-: water: sodium hydroxide: ethanol: hydrochloric acid: 1% hydrochloric acid=1:4 ~ 6:0.1 ~ 0.3:0.1 ~ 0.5:0.5 ~ 2:5 ~ 8.
891g water, 37.5g sodium hydroxide, 35.6g ethanol stirring intensification is added in 2L there-necked flask, be heated to 75 DEG C, the chloro-5-iodo ethyl benzoate of 2-of control temperature dropping 213g 30 minutes, diatomite filtration is passed through after reacting completely, filtrate adds 210ml hydrochloric acid stirring and adjusting PH=1, stirs, and filters, filter cake 1200g1% hydrochloric acid stirring to pulp 30 minutes, filters.50 DEG C of vacuum-drying products, vacuum degree control >-0.085MPa, time of drying, 6 ~ 8h, dried to obtain product 156.2g, and yield is 80.6%.
Based on the production method of the present embodiment, after reacting three steps, the total recovery of product can reach 70%, and product purity is up to 98%.
Claims (4)
1. the synthetic method of the chloro-5-iodo-benzoic acid of 2-, comprise iodo, substitution reaction, mulberry obtains mayer reaction and hydrolysis reaction, it is characterized in that: described iodo, substitution reaction is for determining that raw material and the reagent mass ratio that feeds intake is methyl o-aminobenzoate: Potassium Iodate: iodinating agent: methylene dichloride: water: S-WAT: ethanol: methanol solution of sodium methylate: acetic acid: water=1:0.4 ~ 0.5:0.8 ~ 1:2 ~ 5:1.5 ~ 3:0.008 ~ 0.01:3 ~ 5:0.25 ~ 0.4:0.02 ~ 0.05:0.08 ~ 0.1, water is added in proportion in reaction flask, iodinating agent stirring and dissolving, to add after Potassium Iodate stirring and dissolving again, then methyl o-aminobenzoate and solvent is added successively, drip acetic acid, controlling dropping temperature is 50 ~ 55 DEG C, add rear stirring 30 ~ 120 minutes, heat temperature raising, temperature is raised to and is incubated after 55 ~ 80 DEG C, arranging soaking time is 2 ~ 3h,
Cool after insulation terminates, after being cooled to 30 ~ 35 DEG C, adding solid sodium sulfite after stirring 15 ~ 30min in proportion and carry out except look, continue to be cooled to 20 ~ 25 DEG C, stratification, is divided into water layer and oil reservoir, adds in proportion after methylene dichloride carries out reextraction and collects oil reservoir;
Merge once, secondary oil reservoir, merging oil reservoir is passed through air distillation, controlling distillation temperature is 35 ~ 60 DEG C, the temperature cooling leftover materials after normal pressure removing cut is 30 ~ 35 DEG C, after adding ethanol stirring and dissolving leftover materials, add sodium methylate and be heated to backflow, insulation 1 ~ 2h, controlling distillation temperature is 82 ~ 83 DEG C, normal pressure boils off the mixture of methyl alcohol and ethanol, slowly acetic acid is dripped by proportioning in residuum, add the water of dosage again, be cooled to 0 ~ 5 DEG C of filtration, filtration gained solid drying under reduced pressure carries out oven dry and obtains 2-amino-5-iodo ethyl benzoate, control the temperature < 30 DEG C of drying under reduced pressure, the pressure of drying under reduced pressure is-0.085MPa, time 6 ~ the 8h of drying under reduced pressure,
Described mulberry obtains mayer reaction for determining that raw material and the reagent mass ratio that feeds intake is 2-amino-5-iodo ethyl benzoate: diazonium salt water: diazonium salt hydrochloric acid: Sodium Nitrite: join sodium salt water: replacement water: replacement hydrochloric acid: cuprous chloride: methylene dichloride: saturated aqueous common salt: bath water: anhydrous sodium sulphate=1:1 ~ 2:2.2 ~ 2.5:0.25 ~ 0.3:0.4 ~ 1:0.4 ~ 1:2 ~ 3:0.1 ~ 0.3:2.5 ~ 4:2 ~ 4:1 ~ 3:0.1 ~ 0.3, water is added in proportion in the first reaction flask, hydrochloric acid stirring and dissolving, divide 3 ~ 6 batches, add 2-amino-5-iodo ethyl benzoate at every turn, control temperature is 20 ~ 25 DEG C and stirs 0.5 ~ 2h, drip sodium nitrite in aqueous solution after temperature being cooled to 0 ~ 5 DEG C and carry out diazotization reaction, the time arranging diazotization reaction is 0.5 ~ 3h, temperature of reaction is < 5 DEG C, reaction terminates rear stirring 0.5 ~ 3h,
In the second reaction flask, add water by proportioning, hydrochloric acid set temperature be at 25 ~ 30 DEG C stir add cuprous chloride, then the diazo liquid that diazotization obtains is added dropwise in reaction soln, dropping terminates rear stirring 1 ~ 2 hour, > 24h is stirred after being heated to 35 DEG C subsequently, when controlling to stir, temperature is 30 ~ 35 DEG C, add methylene dichloride by proportioning to stir 15 ~ 45 minutes, stratification, washes twice altogether, merge once, after secondary oil reservoir, with diatomite filtration filtering mantoquita, after filtering, filtrate adds saturated common salt water washing standing twice by proportioning, each washing leaves standstill after 15 ~ 45 minutes and is divided into water layer and oil reservoir in 15-30 minute, water washing stratification is added by proportioning with layer, stir 15 ~ 30 minutes, leave standstill 15 ~ 30 minutes, merge oil reservoir, anhydrous sodium sulphate drying is added by proportioning, filter, underpressure distillation boils off solvent, the time arranging underpressure distillation is 0.5 ~ 2.5h, the pressure of underpressure distillation is >-0.085MPa, the temperature of underpressure distillation is < 20 DEG C, finally obtain the chloro-5-iodo ethyl benzoate of product 2-,
Described hydrolysis reaction is for determining that raw material and the reagent mass ratio that feeds intake is the chloro-5-iodo ethyl benzoate of 2-: water: sodium hydroxide: ethanol: hydrochloric acid: 1% hydrochloric acid=1:4 ~ 6:0.1 ~ 0.3:0.1 ~ 0.5:0.5 ~ 2:5 ~ 8;
First in reaction flask, add water, sodium hydroxide and ethanol heat temperature raising while stirring, be heated to 75 ~ 80 DEG C, control temperature drips the chloro-5-iodo ethyl benzoate of 2-and reacts at 75 ~ 80 DEG C, diatomite filtration is passed through after reacting completely, the filtrate filtered out under agitation adds hydrochloric acid by proportioning, filtrate pH is regulated to be 1 ~ 2, filter after continuing stirring 0.5 ~ 1h, 1% hydrochloric acid stirring to pulp of filter cake dosage 2 ~ 3 times, each making beating 30 ~ 35 minutes, again filter, filtration gained solid drying under reduced pressure carries out oven dry and obtains the chloro-5-iodo-benzoic acid of 2-, the temperature controlling drying under reduced pressure is < 50 DEG C, the pressure of drying under reduced pressure is >-0.085MPa, the time of drying under reduced pressure is 6 ~ 8h.
2. the synthetic method of the chloro-5-iodo-benzoic acid of 2-according to claim 1, is characterized in that: the iodinating agent in described iodo, substitution reaction is iodine or salt compounded of iodine.
3. the synthetic method of the chloro-5-iodo-benzoic acid of 2-according to claim 1, is characterized in that: the solvent in described iodo, substitution reaction and the reaction of Sang get mayer is methylene dichloride, tetrahydrofuran (THF) or DMF.
4. the synthetic method of the chloro-5-iodo-benzoic acid of 2-according to claim 1, is characterized in that: in described iodo, substitution reaction, the density of sodium methylate is 27.6 ~ 30%.
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