CN102079688A - Method for preparing 2,3-dichlorotoluene - Google Patents
Method for preparing 2,3-dichlorotoluene Download PDFInfo
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Abstract
The invention discloses a method for preparing 2,3-dichlorotoluene. The method comprises the following steps of: performing condensation on o-toluidine serving as an initiative raw material and urea to obtain N,N'-di(tolyl) urea; forming a sulfonic blocking group at an amino para-position through sulfonation; performing chlorination, removing carbonyl through hydrolysis and removing the blocking group through hydrolysis to obtain 2-chlorine-6-methylaniline; and performing diazotization and a Sandmeyer reaction to synthesize 2,3-dichlorotoluene to obtain the product. The method has the advantages of environmental friendliness, simple process, low cost and the like.
Description
Technical field
The present invention relates to the method for the important intermediate of synthetic lamotrigine, refer in particular to a kind of 2, the preparation method of 3-toluene dichloride.
Background technology
Lamotrigine (Lamotrigine) is a kind of novel special efficacy antiepileptic drug, and it is formulated in 1985 by Britain Wellcome company, and 2, the 3-toluene dichloride is the important intermediate of synthetic lamotrigine.At present, there are more than 5,000 ten thousand epileptics in the whole world, and the demand of antiepileptic drug is sizable.Exploitation in recent decades novel anti epilepsy efficacy-enhancing ingredient has more efficiently played countries in the world pharmaceuticals researchers' close attention.
In the known technology, 2, the synthetic route of 3-toluene dichloride:
1, people such as external C.S.Marvel proposes Synthetic 2, the method of 3-toluene dichloride is: begin to obtain 3-nitro-2-toluene(mono)chloride through the Sandmeyer reaction from 3-nitro-2-phenylmethylamine, with the tin reduction method nitroreduction is become amino then, obtain 2 through a Sandmeyer reaction again, the 3-toluene dichloride, but total recovery has only 28%.(C.S.Marvel，C.G.Overberger，R.E.Allen，etc.The?preparation?and?polymerization?of?the?six?nuclear?isomeric?dichlorostyrenes[J].J?Am?Chem?Soc.1946，68：861～864)。Reaction equation is as follows:
2,2 of domestic Deng Hong proposition, the synthetic method of 3-toluene dichloride is: begin through the nitrated 3-nitro-2-phenylmethylamine that gets from Ortho Toluidine cheap and easy to get, carry out the Sandmeyer reaction then and obtain 3-nitro-2-toluene(mono)chloride, with iron powder reducing nitroreduction is become amino again, obtain 2, the 3-toluene dichloride through a Sandmeyer reaction again.This synthetic route from Ortho Toluidine begin with the synthetic route of foreign literature report relatively, many preparations of a step 3-nitro-2-phenylmethylamine.In addition, will adopt tin reduction method (yield is 47%) to be improved to the employing iron powder reducing in the foreign literature, yield brings up to 85%.But total recovery still has only 25.8%.(Deng Hong. the study on the synthesis of lamotrigine and intermediate thereof [D]. the Master of Science degree paper .2002:6 of University Of Xiangtan～8).Reaction equation is as follows:
Deng Hong has also mentioned an other route; this route is that the low-cost Ortho Toluidine of employing is a raw material equally; obtain 3-methyl-4 aminobenzene sulfonamide except that behind the deacetylate down by its acetylize, sulfonating chlorinating, ammonia being separated with acidic conditions; envelope is fallen amino contraposition; when guaranteeing chlorination chlorine on the ortho position of amino; after taking off sulfoamido, hydrolysis obtains 2-amino-3-toluene(mono)chloride then; afterwards again by diazotization reaction, Sandmeyer reaction; obtain 2 thereby change amino into chlorine, the 3-toluene dichloride.Reaction equation is as follows:
It is very low that Deng Hong obtains this step yield of 2-amino-3-toluene(mono)chloride in vitriol oil hydrolysis, so after the Sandmeyer reaction is converted into 2 with 2-amino-3-toluene(mono)chloride, this step reaction of 3-toluene dichloride does not go on.Though also attempt with replacing chlorinating agent, changing the concentration and the hydrolysis time of the vitriol oil in the hydrolysis reaction and utilize sulfonic group to seal amino contraposition, Ortho Toluidine is converted into after 3-methyl-4-aniline sulfonic acid, obtain 2 through chlorination, hydrolysis, Sandmeyer reaction, methods such as 3-toluene dichloride, regrettably this reaction scheme does not draw logical all the time.
Above-mentioned about 2, in the report of 3-toluene dichloride synthetic route, people's such as C.S.Marvel synthetic route raw material is difficult to obtain, and price is expensive, and yield is low; Though the synthetic route of Deng Hong is from Ortho Toluidine cheap and easy to get, the first step is synthesized in 3-nitro-2-phenylmethylamine reaction and is used a large amount of aceticanhydrides, wet distillation process length consuming time, and also the yield in this step has only 50%.Therefore, it is short as far as possible need to propose a kind of synthetic route, and the synthetic cost is low as far as possible, and be beneficial to realize industrialized 2, the preparation method of 3-toluene dichloride.
Summary of the invention
The technical problem to be solved in the present invention provides a kind of 2, the preparation method of 3-toluene dichloride, the characteristics of this method are: with Ortho Toluidine and urea is starting raw material, adopt the synthetic route different with forefathers, through steps such as condensation, sulfonation, chlorination, hydrolysis, diazotization, Sandmeyer reactions, preparation 2, the 3-toluene dichloride.Reaction conditions is gentle, and is simple to operate, and productive rate is higher.
The technical problem to be solved in the present invention is realized by following scheme: 2; the preparation method of 3-toluene dichloride is characterized in that: with Ortho Toluidine and urea is starting raw material, through condensation; get N; N '-two (o-tolyl) urea is made N through sulfonation, N '-two (2-chloro-6 aminomethyl phenyls) urea-4; 4 '-disulfonic acid; obtain 2-chloro-6-monomethylaniline through chlorination, hydrolysis decarburization acyl group, hydrolysis desulfonation blockage group again, after diazotization, Sandmeyer reaction make 2, the 3-toluene dichloride.
Present method preparation 2, the total reaction equation of 3-toluene dichloride is as follows:
The present invention also comprises following scheme:
Is that raw material and urea reaction generate N with the Ortho Toluidine, the reaction conditions of N '-two (o-tolyl) urea is: under the situation that adds the zinc granule protection, solvent can be selected dimethylbenzene, a kind of in the primary isoamyl alcohol; The consumption of urea is 30～60 times of Ortho Toluidine weight; Thermotonus is 0 ℃～138 ℃, and better temperature of reaction is 130 ℃～138 ℃; Reaction times is 0h～26h.
N, the sulfonation of N '-two (o-tolyl) urea generates N, N '-two (o-tolyl) urea-4,4 '-reaction conditions of disulfonic acid is: sulphonating agent is to contain H
2SO
4At the vitriol oil more than 95%, or contain free SO
3At the oleum below 10%; The consumption of sulphonating agent is N, 5～9 times of N '-two (o-tolyl) urea weight; Sulfonation temperature is 50 ℃～80 ℃; Sulfonation time 0h～6h.
N, N '-two (o-tolyl) urea-4,4 '-ring of disulfonic acid on chlorination generate N, N '-two (2-chloro-6 aminomethyl phenyls) urea-4,4 '-reaction conditions of disulfonic acid is: chlorizating agent is a chlorine, chlorine and N, N '-two (o-tolyl) urea-4,4 '-mol ratio of disulfonic acid is 2～6: 1; The chlorination medium is 1～10%HCl solution; The consumption of catalyzer iron powder is 0.5～1.5%; Temperature of reaction keeps 20～40 ℃; Reaction times 1～20h.
N, N '-two (2-chloro-6 aminomethyl phenyls) urea-4,4 '-reaction conditions that disulfonic acid hydrolysis decarburization acyl group generates 3-chloro-4-amino-5-toluene sulfonic acide is: hydrolysis medium is to contain H
2SO
410～75% and contain HCl at the aqueous solution below 5%; Hydrolysis temperature is at 90 ℃～110 ℃; Hydrolysis time is 1～5h, logical noble gas protection during hydrolysis.
The reaction conditions that 3-chloro-4-amino-5-toluene sulfonic acide hydrolysis desulfonation generates 2-chloro-6-monomethylaniline is: hydrolysis medium is to contain H
2SO
4The aqueous solution 20～75%, hydrolysis temperature are 120 ℃～180 ℃, hydrolysis time 1～15h, logical noble gas protection during hydrolysis.
2-chloro-6-monomethylaniline and Sodium Nitrite carry out diazotization reaction, carry out the Sandmeyer reaction with CuCl again and generate 2, the reaction conditions of 3-toluene dichloride is: logical nitrogen protection, the mol ratio of 20%～30% hydrochloric acid consumption and 2-chloro-6-monomethylaniline is 2.5～6.1, the mol ratio of Sodium Nitrite and 2-chloro-6-monomethylaniline is 1～1.3, and the diazotization reaction controlled temperature is at 0～10 ℃; The mol ratio of cuprous chloride and 2-chloro-6-monomethylaniline is 2.65～1; decomposing the mixture Heating temperature is 40～80 ℃, emits up to no longer including nitrogen, and heating in water bath to the churning time of boiling is 1h～3h; add the protection of metal shot copper, the catalyzer cuprous chloride is reclaimed in the reaction back.
Advantage of the present invention is: agents useful for same is conventional chemical reagent, and is cheap; Each step operation is not loaded down with trivial details, and condition is not harsh yet, realizes suitability for industrialized production easily, and can improve the rate of output, reduces cost.Have environmental friendliness, simple, the low cost and other advantages of technology.
Description of drawings
Accompanying drawing 1 is preparation technology's schema of the present invention
Embodiment
Embodiment 1: adding Ortho Toluidine 43ml, urea 18g and dimethylbenzene 170ml are warming up to 138 ℃ in the 500ml flask with three necks,round bottom of stirring, thermometric and reflux is housed, and back flow reaction 7 hours is poured out while hot.Under agitation be chilled to normal temperature then, filter, filter cake washs, drains, dries with dimethylbenzene, again with massive laundering wash, drain, dry white, needle-shaped crystals 42.90g, in Ortho Toluidine, N, N '-two (o-tolyl) urea yield 89.40%.
67mL sulfuric acid is poured in the 500mL there-necked flask that thermometer, device for recovering tail gas are housed, take by weighing the N of 24.00g, N '-two (o-tolyl) urea, stir and add in the solution down in batches, add temperature and be no more than 50 ℃, wait until N, after N '-two (o-tolyl) urea all dissolves, temperature keeps 65 ℃ of heating 6 hours, stops heating.Obtain N, N '-two (o-tolyl) urea-4,4 '-disulfonic acid.Add 300mL water, 160mL dilute hydrochloric acid and 0.28g iron powder, logical chlorine (laboratory self-control: potassium permanganate and hydrochloric acid reaction) reaction, temperature of reaction remains on 35 ℃; behind the reaction 12h; obtain N, N '-two (2-chloro-6 aminomethyl phenyls) urea-4,4 '-disulfonic acid; the assembling reflux; feed nitrogen protection, reaction solution slowly is warming up to 107 ℃, insulation hydrolysis 3h; hydrating solution is put into autoclave internal heating to 175 ℃, reaction 12h.Logical nitrogen carries out steam distillation, collects distillate, uses CH again
2Cl
2Extraction, extraction liquid boils off CH with Rotary Evaporators
2Cl
2Separate product 2-chloro-6-monomethylaniline 15.78g, from N, N '-two (o-tolyl) urea is 55.76% to the yield of 2-chloro-6-monomethylaniline.
In the 100ml there-necked flask of thermometer, prolong and dropping funnel is housed, add 2-chloro-6-monomethylaniline 3.77g and water 12ml, logical nitrogen protection is stirred down and is dripped concentrated hydrochloric acid 12ml, slowly is heated to 90 ℃, makes it whole dissolvings, stops logical nitrogen protection.Change the protection of adding metal shot copper into, be cooled to 1 ℃, and maintain under this temperature, drip the aqueous solution (6ml) that contains Sodium Nitrite (2.286g), after slowly dropwising, continue to stir 40 minutes.Take by weighing cuprous chloride 4.5g during this time, slowly be added to about 0 ℃, cold concentrated hydrochloric acid 15ml, make resolution of precipitate.Above-mentioned filtrate slowly is added in the chilled cuprous chloride hydrochloric acid soln, and the limit edged stirs, and separates out red complex soon, after adding, and standing over night under the room temperature.Then it is changed over to the 250ml there-necked flask, water-bath slowly is heated to 60 ℃ under stirring, and decomposes mixture, emits up to no longer including nitrogen, continues heating in water bath was stirred 2 hours to boiling.Carry out steam distillation then, until no longer including 2, the 3-toluene dichloride steams, and collects distillate (about 400ml).Distillate with dichloromethane extraction after, use successively 10%NaOH solution 10ml, water 10ml, dilute sulphuric acid (20%) 10ml and water 10ml each the washing once.CH
2Cl
2Layer boils off CH through Rotary Evaporators
2Cl
2, get water white transparency product 2,3-toluene dichloride 3.33g.From 2-chloro-6-monomethylaniline to 2, the single step yield of 3-toluene dichloride is 77.67%.
Embodiment 2: take by weighing 24.00 N, N '-two (o-tolyl) urea is put into the 1000ml there-necked flask, pours 10% the oleum of 62ml into dropping funnel, dropwise add temperature and be no more than 50 ℃, dissolving N, N '-two (o-tolyl) urea, by the time N, after N '-two (o-tolyl) urea all dissolved, temperature kept 65 ℃ of heating 6 hours, stops heating. obtain N, N '-two (o-tolyl) urea-4,4 '-disulfonic acid.Add 300ml water, 160ml dilute hydrochloric acid and 0.56g iron powder, logical chlorine, Heating temperature remains on 35 ℃, reaction 12h.Obtain N, N '-two (2-chloro-6 aminomethyl phenyls) urea-4,4 '-disulfonic acid, the assembling reflux, logical nitrogen protection slowly is warming up to 107 ℃ with reaction solution, behind the insulation hydrolysis 3h, with solution at autoclave internal heating to 175 ℃.Reacted 10 hours.The cooling back is neutralized to neutrality with yellow soda ash, carries out steam distillation then, collects distillate, uses CH again
2Cl
2Extraction, extraction liquid boils off CH in water-bath
2Cl
2Separate product 2-chloro-6-monomethylaniline 10.61g, with N, N '-two (o-tolyl) urea meter, the yield 37.48% that 2-chloro-6-monomethylaniline is total.；
Embodiment 3: take by weighing 24.00 N, N '-two (o-tolyl) urea is put into the 1000ml there-necked flask, pours 98% the vitriol oil of 67ml into dropping funnel, dropwise add temperature and be no more than 50 ℃, dissolving N, N '-two (o-tolyl) urea, by the time N, after N '-two (o-tolyl) urea all dissolved, temperature kept 65 ℃ of heating 6 hours, stops heating. obtain N, N '-two (o-tolyl) urea-4,4 '-disulfonic acid.Add 300ml water, 160ml dilute hydrochloric acid and 0.56g iron powder, logical chlorine, Heating temperature remains on 35 ℃, reaction 12h.Obtain N, N '-two (2-chloro-6 aminomethyl phenyls) urea-4,4 '-disulfonic acid, the assembling reflux, logical nitrogen protection slowly is warming up to 107 ℃ with reaction solution, behind the insulation hydrolysis 3h, with solution at autoclave internal heating to 175 ℃.Reacted 10 hours.The cooling back is neutralized to neutrality with yellow soda ash, carries out steam distillation then, collects distillate, uses CH again
2Cl
2Extraction, extraction liquid boils off CH in water-bath
2Cl
2Separate product 2-chloro-6-monomethylaniline 10.53g, with N, N '-two (o-tolyl) urea meter, the yield 37.17% that 2-chloro-6-monomethylaniline is total.；
Embodiment 4: take by weighing 24.00 N, N '-two (o-tolyl) urea is put into the 1000ml there-necked flask, pours 2% the oleum of 64ml into dropping funnel, dropwise add temperature and be no more than 50 ℃, dissolving N, N '-two (o-tolyl) urea, by the time N, after N '-two (o-tolyl) urea all dissolved, temperature kept 65 ℃ of heating 6 hours, stops heating. obtain N, N '-two (o-tolyl) urea-4,4 '-disulfonic acid.Add 300ml water, 160ml dilute hydrochloric acid and 0.56g iron powder, logical chlorine, Heating temperature remains on 35 ℃, reaction 12h.Obtain N, N '-two (2-chloro-6 aminomethyl phenyls) urea-4,4 '-disulfonic acid, the assembling reflux, logical nitrogen protection slowly is warming up to 107 ℃ with reaction solution, behind the insulation hydrolysis 3h, with solution at autoclave internal heating to 175 ℃.Reacted 10 hours.The cooling back is neutralized to neutrality with yellow soda ash, carries out steam distillation then, collects distillate, uses CH again
2Cl
2Extraction, extraction liquid boils off CH in water-bath
2Cl
2Separate product 2-chloro-6-monomethylaniline 10.20g, with N, N '-two (o-tolyl) urea meter, the yield 36.06% that 2-chloro-6-monomethylaniline is total.；
Embodiment 5: press embodiment 1, sulfonation reaction adds N, N '-two (o-tolyl) urea meter 24g, 2% oleum 108ml gets product 2-chloro-6-monomethylaniline 10.05g with N, N '-two (o-tolyl) urea meter, the yield 35.53% that 2-chloro-6-monomethylaniline is total.
Embodiment 6: press embodiment 1, in the chlorination reaction process, do not add water and hydrochloric acid, directly logical chlorine gets product 2-chloro-6-monomethylaniline 5.17g with N, N '-two (o-tolyl) urea meter, the yield 18.27% that 2-chloro-6-monomethylaniline is total.
Embodiment 7: press embodiment 1, in two one-step hydrolysis processes, obstructed noble gas protection gets product 2-chloro-6-monomethylaniline 10.61g with N, N '-two (o-tolyl) urea meter, the yield 37.5% that 2-chloro-6-monomethylaniline is total.
Embodiment 8: press embodiment 1, when diazotization reaction, the protection of obstructed noble gas, product 2,3-toluene dichloride 2.93g is in 2-chloro-6-monomethylaniline, 2,3-toluene dichloride single step yield is 72.4%, the product color and luster be a redness.
Embodiment 9: press embodiment 1, Sandmeyer when reaction, do not add the shot copper protection, product 2,3-toluene dichloride 10.2g is in 2-chloro-6-monomethylaniline, 2,3-toluene dichloride single step yield is 76.4%, the product color and luster is faint yellow.
Embodiment 10: press embodiment 1, when diazotization reaction, when temperature of reaction is 10 ℃, product 2,3-toluene dichloride 2.57g is in 2-chloro-6-monomethylaniline, 2,3-toluene dichloride single step yield is 39.5%.
Claims (7)
1.2; the preparation method of 3-toluene dichloride is characterized in that: with Ortho Toluidine and urea is starting raw material, through condensation; get N; N '-two (o-tolyl) urea is made N through sulfonation, N '-two (2-chloro-6 aminomethyl phenyls) urea-4; 4 '-disulfonic acid; obtain 2-chloro-6-monomethylaniline through chlorination, hydrolysis decarburization acyl group, hydrolysis desulfonation blockage group again, after diazotization, Sandmeyer reaction make 2, the 3-toluene dichloride.
2. according to claim 12, the preparation method of 3-toluene dichloride is characterized in that: be that raw material and urea reaction generate N with the Ortho Toluidine, the reaction conditions of N '-two (o-tolyl) urea is: under the situation that adds the zinc granule protection, solvent can be selected dimethylbenzene, a kind of in the primary isoamyl alcohol; The consumption of urea is 30～60 times of Ortho Toluidine weight; Thermotonus is 0 ℃～138 ℃; Reaction times is 0h～26h.
3. according to claim 12, the preparation method of 3-toluene dichloride is characterized in that: N, and the sulfonation of N '-two (o-tolyl) urea generates N, N '-two (o-tolyl) urea-4,4 '-reaction conditions of disulfonic acid is: sulphonating agent is to contain H
2SO
4At the vitriol oil more than 95%, or contain free SO
3At the oleum below 10%; The consumption of sulphonating agent is N, 5～9 times of N '-two (o-tolyl) urea weight; Sulfonation temperature is 50 ℃～80 ℃; Sulfonation time 0h～6h.
4. according to claim 12, the preparation method of 3-toluene dichloride, it is characterized in that: N, N '-two (o-tolyl) urea-4,4 '-ring of disulfonic acid on chlorination generate N, N '-two (2-chloro-6 aminomethyl phenyls) urea-4,4 '-reaction conditions of disulfonic acid is: chlorizating agent is a chlorine, chlorine and N, N '-two (o-tolyl) urea-4,4 '-mol ratio of disulfonic acid is 2～6: 1; The chlorination medium is 1～10%HCl solution; The consumption of catalyzer iron powder is 0.5～1.5%; Temperature of reaction keeps 20～40 ℃; Reaction times 1～20h.
5. according to claim 12; the preparation method of 3-toluene dichloride; it is characterized in that: N, N '-two (2-chloro-6 aminomethyl phenyls) urea-4,4 '-reaction conditions that disulfonic acid hydrolysis decarburization acyl group generates 3-chloro-4-amino-5-toluene sulfonic acide is: hydrolysis medium is to contain H
2SO
410～75% and contain HCl at the aqueous solution below 5%; Hydrolysis temperature is at 90 ℃～110 ℃; Hydrolysis time is 1～5h, logical noble gas protection during hydrolysis.
6. according to claim 12, the preparation method of 3-toluene dichloride is characterized in that: the reaction conditions that 3-chloro-4-amino-5-toluene sulfonic acide hydrolysis desulfonation generates 2-chloro-6-monomethylaniline is: hydrolysis medium is to contain H
2SO
4The aqueous solution 20～75%, hydrolysis temperature are 120 ℃～180 ℃, hydrolysis time 1～15h, logical noble gas protection during hydrolysis.
7. according to claim 12, the preparation method of 3-toluene dichloride, it is characterized in that: 2-chloro-6-monomethylaniline and Sodium Nitrite carry out diazotization reaction, carry out the Sandmeyer reaction with CuCl again and generate 2, the reaction conditions of 3-toluene dichloride is: logical nitrogen protection, 20%～30% hydrochloric acid consumption is 2.5～6.1 of a 2-chloro-6-monomethylaniline mol ratio, and the mol ratio of Sodium Nitrite and 2-chloro-6-monomethylaniline is 1～1.3, and the diazotization reaction controlled temperature is at 0～10 ℃; The mol ratio of cuprous chloride and 2-chloro-6-monomethylaniline is 2.65～1; decomposing the mixture Heating temperature is 40～80 ℃, emits up to no longer including nitrogen, and heating in water bath to the churning time of boiling is 1h～3h; add the protection of metal shot copper, the catalyzer cuprous chloride is reclaimed in the reaction back.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106748627A (en) * | 2016-11-14 | 2017-05-31 | 苏州市罗森助剂有限公司 | A kind of method that one kettle way prepares 3,5 dimethyl bromobenzenes |
| CN106831457A (en) * | 2017-02-28 | 2017-06-13 | 上海微巨实业有限公司 | A kind of new preparation process of the hydroxy acetophenone of 3 amino 2 |
| CN112679364A (en) * | 2020-12-29 | 2021-04-20 | 山东铂源药业有限公司 | Synthetic method of dasatinib key raw material 2-chloro-6-methylaniline |
-
2011
- 2011-01-28 CN CN201110041223.9A patent/CN102079688B/en not_active Expired - Fee Related
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106748627A (en) * | 2016-11-14 | 2017-05-31 | 苏州市罗森助剂有限公司 | A kind of method that one kettle way prepares 3,5 dimethyl bromobenzenes |
| CN106831457A (en) * | 2017-02-28 | 2017-06-13 | 上海微巨实业有限公司 | A kind of new preparation process of the hydroxy acetophenone of 3 amino 2 |
| CN106831457B (en) * | 2017-02-28 | 2019-01-08 | 上海微巨实业有限公司 | A kind of preparation method of 3- amino -2- hydroxy acetophenone |
| CN112679364A (en) * | 2020-12-29 | 2021-04-20 | 山东铂源药业有限公司 | Synthetic method of dasatinib key raw material 2-chloro-6-methylaniline |
| CN112679364B (en) * | 2020-12-29 | 2022-11-18 | 山东铂源药业股份有限公司 | Synthetic method of dasatinib key raw material 2-chloro-6-methylaniline |
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