CN102079688A - Method for preparing 2,3-dichlorotoluene - Google Patents

Abstract

The invention discloses a preparation method of 2,3-dichlorotoluene. The method uses o-toluidine as a starting material to condense with urea to obtain N,N'-bis(o-tolyl)urea, and then Sulfonation forms a sulfonic blocking group at the para-position of the amino group, and then chlorination, hydrolysis decarboxylation, hydrolysis deblocking group to obtain 2-chloro-6-methylaniline, and synthesis of 2 through diazotization and Sandmeyer reaction, 3-Dichlorotoluene gives the product. The invention has the advantages of environmental friendliness, simple process, low cost and the like.

Description

2, the preparation method of 3-dichlorotoluene

technical field

The invention relates to a method for synthesizing an important intermediate of lamotrigine, in particular to a method for preparing 2,3-dichlorotoluene.

Background technique

Lamotrigine (Lamotrigine) is a new type of specific antiepileptic drug, which was created by the British Wellcome Company in 1985, and 2,3-dichlorotoluene is an important intermediate for the synthesis of Lamotrigine. At present, there are more than 50 million epilepsy patients in the world, and the demand for antiepileptic drugs is considerable. In recent decades, the development of new and more efficient antiepileptic drugs has aroused the close attention of drug researchers all over the world.

In the known technology, the synthetic route of 2,3-dichlorotoluene:

1. Foreign C.S.Marvel et al. proposed the method of synthesizing 2,3-dichlorotoluene: starting from 3-nitro-2-aminotoluene through Sandmeyer reaction to obtain 3-nitro-2-chlorotoluene, and then using tin reduction method The nitro group was reduced to an amino group, and 2,3-dichlorotoluene was obtained through a Sandmeyer reaction, but the total yield was 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). The reaction equation is as follows:

2. The synthesis method of 2,3-dichlorotoluene proposed by Deng Hong in China is: starting from the cheap and easy-to-obtain o-toluidine to obtain 3-nitro-2-aminotoluene through nitration, and then carry out Sandmeyer reaction to obtain 3-nitrotoluene Base-2-chlorotoluene, and then reduce the nitro group to an amino group with iron powder reduction, and then undergo a Sandmeyer reaction to obtain 2,3-dichlorotoluene. Compared with the synthetic routes reported in foreign literature, this synthetic route starts from o-toluidine, and has one more step of preparation of 3-nitro-2-aminotoluene. In addition, the tin reduction method (yield 47%) used in foreign literature was improved to iron powder reduction, and the yield increased to 85%. But the total yield is still only 25.8%. (Deng Hong. Synthesis of lamotrigine and its intermediates [D]. Master of Science Dissertation of Xiangtan University. 2002: 6-8). The reaction equation is as follows:

Deng Hong also mentioned another route, which also uses cheap o-toluidine as a raw material, and obtains 3-methyl- 4 Aminobenzenesulfonamide, seal off the para-position of the amino group, ensure that there is a chlorine in the ortho position of the amino group during chlorination, and then remove the sulfonamide group by hydrolysis to obtain 2-amino-3-chlorotoluene, and then pass the diazo Amino reaction, Sandmeyer reaction, the amino group is converted to chlorine to obtain 2,3-dichlorotoluene. The reaction equation is as follows:

Deng Hong obtained 2-amino-3-chlorotoluene by hydrolysis of concentrated sulfuric acid with a very low yield, so the last step of converting 2-amino-3-chlorotoluene into 2,3-dichlorotoluene by Sandmeyer reaction was not carried out. go down. Although it is also attempted to replace the chlorinated reagent, change the concentration of concentrated sulfuric acid in the hydrolysis reaction and the hydrolysis time, and use the sulfonic acid group to block the amino para-position, the o-toluidine is converted into 3-methyl-4-aminobenzenesulfonic acid Afterwards, 2,3-dichlorotoluene was obtained through chlorination, hydrolysis, and Sandmeyer reaction. Unfortunately, this reaction route has not been pulled through.

In the above-mentioned report on the synthesis route of 2,3-dichlorotoluene, the raw materials of the synthesis route of C.S. Marvel et al. are not easy to obtain, the price is expensive, and the yield is low; although Deng Hong’s synthesis route starts from the cheap and easy-to-obtain o-toluidine , but a large amount of acetic anhydride is used in the first step of synthesizing 3-nitro-2-aminotoluene, the steam distillation process takes a long time, and the yield of this step is only 50%. Therefore, it is necessary to propose a method for preparing 2,3-dichlorotoluene with a synthetic route as short as possible, a synthetic cost as low as possible, and an industrialized 2,3-dichlorotoluene.

Contents of the invention

The technical problem to be solved in the present invention is to provide a kind of preparation method of 2,3-dichlorotoluene, the characteristics of this method are: take o-toluidine and urea as starting raw materials, adopt different synthetic routes from the predecessors, through Condensation, sulfonation, chlorination, hydrolysis, diazotization, Sandmeyer reaction and other steps to prepare 2,3-dichlorotoluene. The reaction conditions are mild, the operation is simple, and the yield is high.

The technical problem to be solved in the present invention is realized by following scheme: 2, the preparation method of 3-dichlorotoluene is characterized in that: take o-toluidine and urea as starting raw materials, through condensation, obtain N, N '-di( o-tolyl)urea, through sulfonation to make N,N'-bis(2-chloro-6-methylphenyl)urea-4,4'-disulfonic acid, then chlorination, hydrolysis decarboxylation, water The blocking group of the sulfonic acid group is removed to obtain 2-chloro-6-methylaniline, and finally 2,3-dichlorotoluene is produced through diazotization and Sandmeyer reaction.

This method prepares 2, and the total reaction equation of 3-dichlorotoluene is as follows:

The present invention also includes the following schemes:

Taking o-toluidine as raw material to react with urea to generate N, the reaction condition of N'-di(o-tolyl)urea is: in the case of adding zinc particle protection, the solvent can be selected xylene, a kind of in isoamyl alcohol; The amount of urea used is 30 to 60 times the weight of o-toluidine; the temperature response is 0°C to 138°C, and the better reaction temperature is 130°C to 138°C; the reaction time is 0h to 26h.

The reaction conditions for the sulfonation of N,N'-bis(o-tolyl)urea to N,N'-bis(o-tolyl)urea-4,4'-disulfonic acid are: the sulfonating agent contains H ₂ SO ₄ Concentrated sulfuric acid above 95%, or fuming sulfuric acid containing free _SO3 below 10%; the amount of sulfonating agent is 5 to 9 times the weight of N,N'-di(o-tolyl)urea; The sulfonation temperature is 50℃～80℃; the sulfonation time is 0h～6h.

Ring chlorination of N,N'-bis(o-tolyl)urea-4,4'-disulfonic acid to generate N,N'-bis(2-chloro-6-methylphenyl)urea-4,4' -The reaction condition of disulfonic acid is: chlorination agent is chlorine gas, and the mol ratio of chlorine gas and N, N'-bis(o-tolyl)urea-4,4'-disulfonic acid is 2～6:1; Chlorination The medium is 1-10% HCl solution; the amount of catalyst iron powder is 0.5-1.5%; the reaction temperature is maintained at 20-40° C.; the reaction time is 1-20 hours.

The reaction conditions for the decarboxylation of N,N'-bis(2-chloro-6-methylphenyl)urea-4,4'-disulfonic acid to generate 3-chloro-4-amino-5-methylbenzenesulfonic acid Yes: The hydrolysis medium is an aqueous solution containing 10-75% _H2SO4 and less than 5% _HCl ; the hydrolysis temperature is 90°C-110°C; the hydrolysis time is 1-5h, and inert gas is used for protection during hydrolysis.

The reaction conditions for the hydrolysis of 3-chloro-4-amino-5-methylbenzenesulfonic acid to remove the sulfonic acid group to generate 2-chloro-6-methylaniline are: the hydrolysis medium is _a 20-75% aqueous solution containing _H2SO4 , The hydrolysis temperature is 120°C~180°C, the hydrolysis time is 1~15h, and the inert gas is used for protection during hydrolysis.

2-Chloro-6-methylaniline undergoes diazotization reaction with sodium nitrite, and then performs Sandmeyer reaction with CuCl to generate 2,3-dichlorotoluene. The reaction conditions are: nitrogen protection, 20% to 30% hydrochloric acid dosage The molar ratio of sodium nitrite to 2-chloro-6-methylaniline is 2.5~6.1, the molar ratio of sodium nitrite to 2-chloro-6-methylaniline is 1~1.3, and the temperature of diazotization reaction is controlled at 0~10℃ ; The molar ratio of cuprous chloride to 2-chloro-6-methylaniline is 2.65~1, the heating temperature of the decomposition complex is 40~80°C, until no nitrogen gas is released, the water bath is heated to boiling and the stirring time is 1h~ 3h, add metal copper particles for protection, and recover the catalyst cuprous chloride after the reaction.

The invention has the advantages that all the reagents used are conventional chemical reagents, and the price is low; the reaction operation of each step is not cumbersome and the conditions are not harsh, it is easy to realize industrialized production, and the production rate can be increased and the cost can be reduced. The invention has the advantages of environmental friendliness, simple process, low cost and the like.

Description of drawings

Accompanying drawing 1 is the preparation process flow chart of the present invention

Detailed ways

Embodiment 1: Add o-toluidine 43ml, urea 18g, and xylene 170ml in the 500ml round-bottom three-neck flask that stirring, measuring temperature and reflux device are housed and heat up to 138 ℃, reflux reaction 7 hours, pour out while hot. Then cool to normal temperature under stirring, filter, the filter cake is washed with xylene, drained, and dried, and then washed with a large amount of water, drained, and dried to obtain 42.90 g of white needle crystals, in terms of o-toluidine, N, The yield of N'-di(o-tolyl)urea was 89.40%.

Pour 67mL of sulfuric acid into a 500mL three-necked flask equipped with a thermometer and an exhaust gas recovery device, weigh 24.00g of N,N'-di(o-tolyl)urea, add it to the solution in batches under stirring, and the addition temperature does not exceed 50°C , after the N,N'-di(o-tolyl)urea was completely dissolved, the temperature was kept at 65° C. for 6 hours, and then the heating was stopped. N,N'-bis(o-tolyl)urea-4,4'-disulfonic acid is obtained. Add 300mL of water, 160mL of dilute hydrochloric acid and 0.28g of iron powder, and react with chlorine gas (self-made in the laboratory: potassium permanganate reacts with hydrochloric acid). The reaction temperature is kept at 35°C. After 12 hours of reaction, N,N'-di(2 -Chloro-6methylphenyl)urea-4,4'-disulfonic acid, assemble the reflux device, pass in nitrogen protection, slowly raise the temperature of the reaction solution to 107°C, keep it warm for 3 hours, and put the hydrolyzed solution into the autoclave Heated to 175°C and reacted for 12h. Steam distillation was carried out with nitrogen gas, the distillate was collected, and then extracted with CH ₂ Cl ₂ , and the extract was evaporated to remove CH ₂ Cl ₂ with a rotary evaporator to obtain 15.78 g of the product 2-chloro-6-methylaniline, which was obtained from N, N The yield of '-di(o-tolyl)urea to 2-chloro-6-methylaniline is 55.76%.

In a 100ml three-neck flask equipped with a thermometer, condenser and dropping funnel, add 3.77g of 2-chloro-6-methylaniline and 12ml of water, protect with nitrogen, add 12ml of concentrated hydrochloric acid dropwise under stirring, and slowly heat to 90°C , so that it was completely dissolved, and the nitrogen protection was stopped. Instead, add metal copper particles for protection, cool to 1°C, and maintain at this temperature, add an aqueous solution (6ml) containing sodium nitrite (2.286g) dropwise, and continue stirring for 40 minutes after the slow addition is complete. During this period, 4.5g of cuprous chloride was weighed, and slowly added to about 0°C, 15ml of cold concentrated hydrochloric acid to dissolve the precipitate. Slowly add the above-mentioned filtrate to the cooled cuprous chloride hydrochloric acid solution, stir while adding, and soon a red complex is precipitated. After the addition, stand overnight at room temperature. Then it was transferred to a 250ml three-neck flask, stirred and heated slowly to 60°C in a water bath to decompose the complex until no nitrogen gas was released, and continued to heat the water bath to boiling and stirred for 2 hours. Then steam distillation was carried out until no more 2,3-dichlorotoluene was evaporated, and the distillate (about 400ml) was collected. After the distillate was extracted with dichloromethane, it was washed successively with 10ml of 10% NaOH solution, 10ml of water, 10ml of dilute sulfuric acid (20%) and 10ml of water. The CH ₂ Cl ₂ layer was evaporated by a rotary evaporator to remove CH ₂ Cl ₂ to obtain 3.33 g of a colorless and transparent product 2,3-dichlorotoluene. The single-step yield from 2-chloro-6-methylaniline to 2,3-dichlorotoluene was 77.67%.

Embodiment 2: Weigh 24.00 N, N'-bis(o-tolyl)urea and put it into a 1000ml three-necked flask, pour 10% oleum of 62ml into the dropping funnel, add dropwise and the temperature does not exceed 50°C , dissolve N, N'-bis(o-tolyl)urea, wait until N,N'-bis(o-tolyl)urea is completely dissolved, keep the temperature at 65°C for 6 hours, stop heating. Get N,N'- Bis(o-tolyl)urea-4,4'-disulfonic acid. Add 300ml of water, 160ml of dilute hydrochloric acid and 0.56g of iron powder, pass chlorine gas, keep the heating temperature at 35°C, and react for 12h. To obtain N,N'-bis(2-chloro-6-methylphenyl)urea-4,4'-disulfonic acid, assemble a reflux device, pass nitrogen protection, slowly raise the temperature of the reaction solution to 107°C, and heat-preserve and hydrolyze for 3h Afterwards, the solution was heated to 175° C. in an autoclave. React for 10 hours. After cooling, use sodium carbonate to neutralize to neutral, then carry out steam distillation _, collect the distillate, and then extract with CH ₂ Cl ₂ , distill the extract in a water bath to remove CH ₂ Cl 2 and separate the product 2-chloro-6-methyl 10.61 g of aniline, based on N,N'-di(o-tolyl)urea, the total yield of 2-chloro-6-methylaniline is 37.48%. ;

Embodiment 3: Weigh 24.00 N, N'-bis(o-tolyl)urea and put it into a 1000ml three-necked flask, pour 67ml of 98% concentrated sulfuric acid into the dropping funnel, add dropwise and the temperature does not exceed 50°C, Dissolve N,N'-di(o-tolyl)urea, wait until N,N'-bis(o-tolyl)urea is completely dissolved, keep the temperature at 65°C for 6 hours, stop heating. Obtain N,N'-di(o-tolyl)urea (o-tolyl)urea-4,4'-disulfonic acid. Add 300ml of water, 160ml of dilute hydrochloric acid and 0.56g of iron powder, pass chlorine gas, keep the heating temperature at 35°C, and react for 12h. To obtain N,N'-bis(2-chloro-6-methylphenyl)urea-4,4'-disulfonic acid, assemble a reflux device, pass nitrogen protection, slowly raise the temperature of the reaction solution to 107°C, and heat-preserve and hydrolyze for 3h Afterwards, the solution was heated to 175° C. in an autoclave. React for 10 hours. After cooling, use sodium carbonate to neutralize to neutral, then carry out steam distillation _, collect the distillate, and then extract with CH ₂ Cl ₂ , distill the extract in a water bath to remove CH ₂ Cl 2 and separate the product 2-chloro-6-methyl 10.53 g of aniline, based on N,N'-di(o-tolyl)urea, the total yield of 2-chloro-6-methylaniline is 37.17%. ;

Example 4: Weigh 24.00 N, N'-bis(o-tolyl)urea and put it into a 1000ml three-necked flask, pour 2% oleum of 64ml into the dropping funnel, add dropwise and the temperature does not exceed 50°C , dissolve N, N'-bis(o-tolyl)urea, wait until N,N'-bis(o-tolyl)urea is completely dissolved, keep the temperature at 65°C for 6 hours, stop heating. Get N,N'- Bis(o-tolyl)urea-4,4'-disulfonic acid. Add 300ml of water, 160ml of dilute hydrochloric acid and 0.56g of iron powder, pass chlorine gas, keep the heating temperature at 35°C, and react for 12h. To obtain N,N'-bis(2-chloro-6-methylphenyl)urea-4,4'-disulfonic acid, assemble a reflux device, pass nitrogen protection, slowly raise the temperature of the reaction solution to 107°C, and heat-preserve and hydrolyze for 3h Afterwards, the solution was heated to 175° C. in an autoclave. React for 10 hours. After cooling, use sodium carbonate to neutralize to neutral, then carry out steam distillation _, collect the distillate, and then extract with CH ₂ Cl ₂ , distill the extract in a water bath to remove CH ₂ Cl 2 and separate the product 2-chloro-6-methyl 10.20 g of aniline, based on N,N'-di(o-tolyl)urea, the total yield of 2-chloro-6-methylaniline is 36.06%. ;

Embodiment 5: press embodiment 1, sulfonation reaction, add N, N'-bis (o-tolyl) urea meter 24g, 2% oleum 108ml, obtain product 2-chloro-6-methylaniline 10.05g Based on N,N'-di(o-tolyl)urea, the total yield of 2-chloro-6-methylaniline is 35.53%.

Embodiment 6: According to Embodiment 1, in the chlorination reaction process, do not add water and hydrochloric acid, directly lead chlorine gas, obtain product 2-chloro-6-methylaniline 5.17g with N, N'-di(o-tolyl)urea Calculated, the total yield of 2-chloro-6-methylaniline is 18.27%.

Example 7: According to Example 1, in the two-step hydrolysis process, without inert gas protection, the product 2-chloro-6-methylaniline 10.61g was calculated as N, N'-di(o-tolyl)urea, 2 - The overall yield of chloro-6-methylaniline is 37.5%.

Example 8: According to Example 1, during the diazotization reaction, without inert gas protection, 2.93 g of the product 2,3-dichlorotoluene was obtained in terms of 2-chloro-6-methylaniline, 2,3-dichlorotoluene The single-step yield of toluene is 72.4%, and the color of the product is red.

Embodiment 9: According to embodiment 1, when Sandmeyer reacts, do not add copper particle protection, obtain product 2,3-dichlorotoluene 10.2g is counted in 2-chloro-6-methylaniline, 2,3-dichlorotoluene mono The step yield is 76.4%, and the color of the product is light yellow.

Example 10: According to Example 1, during the diazotization reaction, when the reaction temperature was 10°C, 2.57 g of the product 2,3-dichlorotoluene was obtained in terms of 2-chloro-6-methylaniline, 2,3- The single-step yield of dichlorotoluene 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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