CN104744338A - Method for synthesizing 6-chlorhydroxyl indole - Google Patents
Method for synthesizing 6-chlorhydroxyl indole Download PDFInfo
- Publication number
- CN104744338A CN104744338A CN201510145735.8A CN201510145735A CN104744338A CN 104744338 A CN104744338 A CN 104744338A CN 201510145735 A CN201510145735 A CN 201510145735A CN 104744338 A CN104744338 A CN 104744338A
- Authority
- CN
- China
- Prior art keywords
- nitrophenyl
- chloro
- acid
- acetic acid
- dichloronitrobenzene
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
The invention relates to a method for synthesizing 6-chlorhydroxyl indole. The synthesizing steps are as follows: (1) preparing 2, 5-dichloronitrobenzene through paradichlorobenzene nitration; (2) synthesizing 2-(4-chlorine-2-nitrobenzophenone) dimethyl malonate by 2, 5-dichloronitrobenzene; (3) synthesizing 4-chlorine-2-nitrophenyl acetic acid by 2, 5-dichloronitrobenzene; and (4) preparing 6-chlorhydroxyl indole by 4-chlorine-2-nitrophenyl acetic acid. By adopting the method, the whole reaction process is mild in condition and easy to control; the safety in the reaction process is increased, the operation is simple and the industrial production can be realized; and the raw materials are simple and easy to obtain, the production cost is reduced, the yield is obviously increased and a foundation for the industrial production is laid.
Description
Technical field
The present invention relates to a kind of preparation method of pharmaceutical intermediate, especially a kind of synthetic method of intermediate 6-chlorine oxindole of medicine Ziprasidone HCl.
Background technology
Ziprasidone HCl (Ziprasidone) is the up-to-date atypia wide spectrum antipsychotic drug of exploitation, is used for the treatment of schizophrenia.This product belongs to serotonin and dopamine-receptor antagonist, particularly strong to 5-HTA2/DAD2 receptor affinity.This medicine oral dosage form and intramuscular injection formulation are gone on the market in Sweden respectively at 1998 and in September, 2000.All good curative effect is had to acute or chronic, onset or Recurrent schizophrenia; To schizophrenia related symptoms (comprise audiovisual illusion, vain hope, motivation shortage and escape society) effectively.Compared with traditional antipsychotics, this medicine, except improving except positive symptom, also can improve negative symptoms, and improve cognitive function, untoward reaction particularly extrapyramidal symptoms alleviates greatly, and tolerance significantly improves; Compared with widely used olanzapine, quinoline Horizon, risperidone etc., this product is to negative symptoms better efficacy or quite, do not cause body weight to increase and Serum Prolactin In Patients rising, side effect is less than existing all antipsychotic drugs that is not true to type.
China in recent years psychosis morbidity constantly increases, and wherein the highest with schizophrenia again, the whole nation estimates at 8,000,000 patients, and antipsychotics kind on market is few.Ziprasidone has significant superiority in curative effect and side effect, in the world can with at present the most salable antipsychotic drug olanzapine and risperidone competitive market in the world, and can greatly reduce costs after exploitation production domesticization, have the wide market space especially at home, so considerable market efficiency will be brought to manufacturer.And the manufacturer of its intermediate 6-chlorine oxindole is little at home, though the synthesis technique about 6-chlorine oxindole has very many reports, but be limited to Safety control and cost factor, be mostly in laboratory stage at present, process characteristic cannot meet suitability for industrialized production.
By retrieval and technology contrast, do not find the patent publication us relevant to patent application of the present invention.
Summary of the invention
Object of the present invention is just the deficiency overcome by technique adjustment in above-mentioned Technology, provide a kind of preparation technology about 6-chlorine oxindole, this technological reaction mild condition, be convenient to control, and owing to laying particular emphasis on the control of reaction process, thus decrease last handling process, simplify technique; Starting material are simple and easy to get, and cost is lower, and product yield is significantly increased, and are suitable for carrying out suitability for industrialized production.
The object of the invention is to be achieved through the following technical solutions:
A synthetic method for 6-chlorine oxindole, step is as follows:
(1) by santochlor nitrated preparation 2,5-dichloronitrobenzene:
Santochlor is dropped in nitric-sulfuric acid, insulation reaction 2-6h under 50-100 DEG C of condition, reaction terminates rear cooling 50-70 DEG C, adds in the frozen water of 0 DEG C by reaction solution, and stir hydrolysis, material additional proportion is reaction solution: the mass ratio of water is 1:0.5-1, filter, obtain 2,5-dichloronitrobenzene solid, this solids wash to neutrality is obtained khaki color solid, 2, the 5-dichloronitrobenzenes that content is greater than 99%;
Wherein, the weight ratio of described santochlor and nitric-sulfuric acid is: 1: 2-5; Described nitric-sulfuric acid is the mixture of the vitriol oil and concentrated nitric acid, the vitriol oil: the weight ratio of concentrated nitric acid is 1: 0.2-0.5;
(2) prepare 2-(the chloro-2-nitrophenyl of 4-) dimethyl malonate by 2,5-dichloronitrobenzene:
Add dimethyl sulfoxide (DMSO) and dimethyl malonate, 2 are added under stirring, 5-dichloronitrobenzene and salt of wormwood, heat temperature raising, 50-100 DEG C of insulation reaction 3-10h, 10-50 DEG C is cooled to after having reacted, reaction solution is added to the water, adding the water yield is: 2, 5-dichloronitrobenzene: the mass ratio of water is 1: 20-35, mass concentration 25-30% hydrochloric acid is added again below 30 DEG C, hydrochloric acid consumption is: 2, 5-dichloronitrobenzene: the mass ratio of hydrochloric acid is 1: 3-5, stir 1-3h, filter, be washed to neutrality, obtaining khaki color solid is 2-(the chloro-2-nitrophenyl of 4-) dimethyl malonate,
Wherein, the weight ratio of 2,5-dichloronitrobenzene and dimethyl malonate and salt of wormwood insulation reaction in dimethyl sulfoxide (DMSO) is: 2,5-dichloronitrobenzene: dimethyl malonate: salt of wormwood=1: 1-3: 1-6; Solvent load is: 2,5-dichloronitrobenzene: the weight ratio of dimethyl sulfoxide (DMSO) is 1: 6-20;
(3) by 2-(4-chloro-2-nitrophenyl) the chloro-2-nitrophenyl-acetic acid of malonic acid dimethyl Lipase absobed 4-:
2-(the chloro-2-nitrophenyl of 4-) dimethyl malonate is added in acetic acid, add mass concentration 20-37% hydrochloric acid again, be heated to 50-100 DEG C, insulated and stirred 3-6h, less than 30 DEG C are cooled to after having reacted, reaction solution being poured in cold water, stirs and be cooled to less than 15 DEG C, filter, being washed to neutral khaki color solid to be the chloro-2-nitrophenyl-acetic acid of 4-;
Wherein, 2-(the chloro-2-nitrophenyl of 4-) dimethyl malonate insulation reaction in acetic acid and hydrochloric acid, its weight ratio is 2-(the chloro-2-nitrophenyl of 4-) dimethyl malonate: acetic acid: hydrochloric acid=1: 1-6: 4-9;
(4) prepare 6-chlorine oxindole by the chloro-2-nitrophenyl-acetic acid of 4-:
The chloro-2-nitrophenyl-acetic acid of 4-is added in acetic acid and methyl alcohol, heat temperature raising 50 ~ 55 DEG C, add iron powder, slowly be warming up to backflow, backflow insulation reaction 2-5h, after reaction terminates, be cooled to less than 30 DEG C, be added to the water to reaction solution, adding the water yield is: the chloro-2-nitrophenyl-acetic acid of 4-: the mass ratio of water is 1: 30-60, add mass concentration 25-30% hydrochloric acid, hydrochloric acid consumption is: the chloro-2-nitrophenyl-acetic acid of 4-: the mass ratio of hydrochloric acid is 1: 3-6, stir 3-4h, lower the temperature less than 15 DEG C, filter, being washed to neutrality, to obtain khaki color solid be 6-chlorine oxindole, the final product being greater than 99% is obtained again by recrystallizing methanol,
Wherein, the chloro-2-nitrophenyl-acetic acid of 4-reacts with iron powder in mixed solvent, and its weight ratio is the chloro-2-nitrophenyl-acetic acid of 4-: iron powder: acetic acid: methyl alcohol=1: 0.5-2: 1-7: 2-5;
And described step (1) middle nitric acid is concentrated nitric acid or nitrosonitric acid.
And the described step (1) middle dichlorobenzene insulation reaction temperature dropped in nitric-sulfuric acid is 70-90 DEG C.
And, described in be filtered into suction filtration.
And, described step (1) in be hydrolyzed in reaction solution, to add cold water after stir 1 hour.
And, described step (1) in santochlor dropped in nitric-sulfuric acid be specially: get the part vitriol oil, under stirring, add santochlor, add under water cooling in the nitric-sulfuric acid be made up of the residue vitriol oil and nitric acid.
The advantage that the present invention obtains and positively effect are:
1, the whole reaction process mild condition of the inventive method, is easy to control; Reaction process security improves, simple to operate, is conducive to realizing suitability for industrialized production; Starting material are simple, be easy to get, and both reduced production cost, yield is also significantly improved, for suitability for industrialized production is laid a good foundation.
2, the step (1) of the inventive method is by technology controlling and process, 2,5-dichloronitrobenzene content in crude product can be made to reach more than 99%, without the need to carrying out recrystallization again, improve yield, reducing production cost, reduces postprocessing working procedures.
3, the step (2) of the inventive method replaces sodium hydride with salt of wormwood, improves security and the operation controllability of reaction, reaction temperature and, product yield is significantly improved, and yield can reach 94%, is conducive to suitability for industrialized production.
4, the step (4) of the inventive method adopts iron powder to instead of glass putty, and be both conducive to reducing production cost, starting material are easy to get, and product yield is also significantly improved, and yield can reach 93%.
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail, but embodiments of the present invention are not limited thereto, and can not limit protection scope of the present invention with following embodiment.
The experimental technique used in following embodiment if no special instructions, is ordinary method; The material used, reagent etc., if no special instructions, all can obtain from commercial channels.
6-chlorine oxindole synthetic route of the present invention is as follows:
Embodiment 1:
A synthetic method for 6-chlorine oxindole, step is as follows:
(1) 2,5-dichloronitrobenzene preparation
The 157ml vitriol oil is added in 1000ml there-necked flask, 196g santochlor is added under stirring, drip under water cooling and prepare nitration mixture by the 60ml vitriol oil and 75ml nitric acid, dropwise, slowly be warmed up to 80-100 DEG C, insulation reaction 2-4 hour, after reaction terminates, be cooled to about 60 DEG C, add 392g cold water, stir 1 hour, suction filtration obtains yellow solid, obtains yellow solid 249.5g, 80 DEG C of hot water fusings, abundant agitator treating is to neutral, and when being cooled to 15 DEG C, suction filtration obtains yellow solid, i.e. 2,5-dichloronitrobenzenes.
Dry 244g, content: be greater than 99% yield 95%.
(2) preparation of 2-(the chloro-2-nitrophenyl of 4-) dimethyl malonate
5000ml there-necked flask adds dimethyl sulfoxide (DMSO) 3000ml and 280g dimethyl malonate, 2 of 251.2g are added under stirring, 5-dichloronitrobenzene and 500g Anhydrous potassium carbonate, slowly be warming up to 85-95 DEG C, insulation reaction 6 ~ 10 hours, cools to 20 DEG C after reaction terminates, adds in 8000ml water, below 30 DEG C, drip about 760 ~ 780ml concentrated hydrochloric acid, drip off stirring 2 hours.Suction filtration is also washed, and obtains khaki color solid 2-(the chloro-2-nitrophenyl of 4-) dimethyl malonate, dries 356g, content: 93.6% yield: 94.9%, without the need to purifying, be directly used in the next step.
(3) preparation of the chloro-2-nitrophenyl-acetic acid of 4-
5000ml there-necked flask adds 822ml acetic acid, 2-(the chloro-2-nitrophenyl of the 4-) dimethyl malonate of 356g is added under stirring, slowly add 1826ml concentrated hydrochloric acid again, finish and be slowly warming up to 90-100 DEG C, insulation reaction 5 ~ 7 hours, less than 30 DEG C are cooled to after having reacted, reaction solution is poured in 4600g cold water, stirs and be cooled to less than 15 DEG C, suction filtration also uses 600ml water washing, obtain khaki color solid, i.e. 4-chlorine 2--nitrophenyl-acetic acid.Dry 305g content: 98.25% yield: 98.4%
(4) preparation of 6-chlorine oxindole
3000ml there-necked flask adds 700ml acetic acid and 700ml methyl alcohol, and add the chloro-2-nitrophenyl-acetic acid of 4-262.5 grams under stirring, heat temperature raising 50 ~ 55 DEG C, add-on is 125g iron powder in batches, finishes, and is slowly warming up to backflow, insulation reaction 2-4 hour.React complete, be cooled to less than 30 DEG C, pour in 13L cold water, add 1.3Lml concentrated hydrochloric acid, stir 3 hours, lower the temperature less than 15 DEG C, suction filtration is also washed with water to neutrality, obtain khaki color solid, i.e. 6-chlorine oxindole, dry 203g content: 98.68% yield: 93.1%.Gained solids with methanol recrystallization, activated carbon decolorizing, crystallisation by cooling, filters, dry 153.8g product 6-chlorine oxindole, content 99.7%.
Embodiment 2:
A synthetic method for 6-chlorine oxindole, step is as follows:
(1) 2,5-dichloronitrobenzene preparation
The 156.7ml vitriol oil is added in 1000ml there-necked flask, 196g santochlor is added under stirring, drip under water cooling and prepare nitration mixture by the 58.8ml vitriol oil and 70ml nitrosonitric acid, exothermic heat of reaction, dropwises, and is slowly warmed up to 80-95 DEG C, insulation reaction 2 hours, be cooled to about 60 DEG C after reaction terminates, add 392g cold water, stir 1 hour, suction filtration obtains yellow solid, obtain yellow solid 257g, 80 DEG C of hot water fusings, abundant agitator treating is to neutral, when being cooled to 15 DEG C, suction filtration obtains yellow solid, i.e. 2,5-dichloronitrobenzenes.Dry 251.2g, content: 99.7% yield 97.6%.
(2) preparation of 2-(the chloro-2-nitrophenyl of 4-) dimethyl malonate
5000ml there-necked flask adds dimethyl sulfoxide (DMSO) 3000ml and 326g dimethyl malonate, 2 of 251.2g are added under stirring, 5-dichloronitrobenzene and 500g Anhydrous potassium carbonate, slowly be warming up to 85-95 DEG C, insulation reaction 6 ~ 10 hours, cools to 20 DEG C after reaction terminates, adds in 8000ml water, below 30 DEG C, drip about 760 ~ 780ml concentrated hydrochloric acid, drip off stirring 2 hours.Suction filtration is also washed, and obtains khaki color solid 2-(the chloro-2-nitrophenyl of 4-) dimethyl malonate, dries 350g, content: 93.7% yield: 93.3%, without the need to purifying, be directly used in the next step.
(3) preparation of the chloro-2-nitrophenyl-acetic acid of 4-
5000ml there-necked flask adds 678ml acetic acid, 2-(the chloro-2-nitrophenyl of the 4-) dimethyl malonate of 356g is added under stirring, slowly add 1826ml concentrated hydrochloric acid again, finish and be slowly warming up to 90-100 DEG C, insulation reaction 5 ~ 7 hours, less than 30 DEG C are cooled to after having reacted, reaction solution is poured in 4600g cold water, stirs and be cooled to less than 15 DEG C, suction filtration also uses 600ml water washing, obtain khaki color solid, i.e. 4-chlorine 2--nitrophenyl-acetic acid.Dry 300g content: 98.25% yield: 93.3%
(4) preparation of 6-chlorine oxindole
3000ml there-necked flask adds 700ml acetic acid and 700ml methyl alcohol, and add the chloro-2-nitrophenyl-acetic acid of 4-262.5 grams under stirring, heat temperature raising 50 ~ 55 DEG C, add-on is 130g iron powder in batches, finishes, and is slowly warming up to backflow, insulation reaction 2-4 hour.React complete, be cooled to less than 30 DEG C, pour in 13L cold water, add 1.3Lml concentrated hydrochloric acid, stir 3 hours, lower the temperature less than 15 DEG C, suction filtration is also washed with water to neutrality, obtain khaki color solid, i.e. 6-chlorine oxindole, dry 204g content: 98.5% yield: 93.5%.Gained solids with methanol recrystallization, activated carbon decolorizing, crystallisation by cooling, filters, dry 155g product 6-chlorine oxindole, content 99.68%.
Embodiment 3:
A synthetic method for 6-chlorine oxindole, step is as follows:
(1) 2,5-dichloronitrobenzene preparation
The 178ml vitriol oil is added in 1000ml there-necked flask, 196g santochlor is added under stirring, drip under water cooling and prepare nitration mixture by the 68ml vitriol oil and 95ml nitric acid, dropwise, slowly be warmed up to 80-100 DEG C, insulation reaction 2-4 hour, after reaction terminates, be cooled to about 60 DEG C, add 450g cold water, stir 1 hour, suction filtration obtains yellow solid, obtains yellow solid 250g, 80 DEG C of hot water fusings, abundant agitator treating is to neutral, and when being cooled to 15 DEG C, suction filtration obtains yellow solid, i.e. 2,5-dichloronitrobenzenes.Dry 239g, content: be greater than 99% yield 92.9%.
(2) preparation of 2-(the chloro-2-nitrophenyl of 4-) dimethyl malonate
5000ml there-necked flask adds dimethyl sulfoxide (DMSO) 3000ml and 370g dimethyl malonate, 2 of 251.2g are added under stirring, 5-dichloronitrobenzene and 500g Anhydrous potassium carbonate, slowly be warming up to 85-95 DEG C, insulation reaction 6 ~ 10 hours, cools to 20 DEG C after reaction terminates, adds in 8000ml water, below 30 DEG C, drip about 760 ~ 780ml concentrated hydrochloric acid, drip off stirring 2 hours.Suction filtration is also washed, and obtains khaki color solid 2-(the chloro-2-nitrophenyl of 4-) dimethyl malonate, dries 348g, content: 93.9% yield: 92.8%, without the need to purifying, be directly used in the next step.
(3) preparation of the chloro-2-nitrophenyl-acetic acid of 4-
5000ml there-necked flask adds 822ml acetic acid, 2-(the chloro-2-nitrophenyl of the 4-) dimethyl malonate of 356g is added under stirring, slowly add 1826ml concentrated hydrochloric acid again, finish and be slowly warming up to 90-100 DEG C, insulation reaction 5 ~ 7 hours, less than 30 DEG C are cooled to after having reacted, reaction solution is poured in 4600g cold water, stirs and be cooled to less than 15 DEG C, suction filtration also uses 600ml water washing, obtain khaki color solid, i.e. 4-chlorine 2--nitrophenyl-acetic acid.Dry 262.5g content: 98.3% yield: 98.4%
(4) preparation of 6-chlorine oxindole
3000ml there-necked flask adds 700ml acetic acid and 700ml methyl alcohol, and add the chloro-2-nitrophenyl-acetic acid of 4-262.5 grams under stirring, heat temperature raising 50 ~ 55 DEG C, add-on is 120g iron powder in batches, finishes, and is slowly warming up to backflow, insulation reaction 2-4 hour.React complete, be cooled to less than 30 DEG C, pour in 13L cold water, add 1.3Lml concentrated hydrochloric acid, stir 3 hours, lower the temperature less than 15 DEG C, suction filtration is also washed with water to neutrality, obtains khaki color solid, i.e. 6-chlorine oxindole, dries 200g content: 98.3% yield: 92%.Gained solids with methanol recrystallization, activated carbon decolorizing, crystallisation by cooling, filters, dry 150g product 6-chlorine oxindole, content 99.5%.
Embodiment 4:
A synthetic method for 6-chlorine oxindole, step is as follows:
(1) 2,5-dichloronitrobenzene preparation
The 198ml vitriol oil is added in 1000ml there-necked flask, 196g santochlor is added under stirring, drip under water cooling and prepare nitration mixture by the 130ml vitriol oil and 128ml nitric acid, dropwise, slowly be warmed up to 80-100 DEG C, insulation reaction 2-4 hour, after reaction terminates, be cooled to about 60 DEG C, add 980g cold water, stir 1 hour, suction filtration obtains yellow solid, obtains yellow solid 232g, 80 DEG C of hot water fusings, abundant agitator treating is to neutral, and when being cooled to 15 DEG C, suction filtration obtains yellow solid, i.e. 2,5-dichloronitrobenzenes.
Dry 226.4g, content: be greater than 99% yield 88%.
(2) preparation of 2-(the chloro-2-nitrophenyl of 4-) dimethyl malonate
5000ml there-necked flask adds dimethyl sulfoxide (DMSO) 3000ml and 502g dimethyl malonate, 2 of 251.2g are added under stirring, 5-dichloronitrobenzene and 700g Anhydrous potassium carbonate, slowly be warming up to 85-95 DEG C, insulation reaction 6 ~ 10 hours, cools to 20 DEG C after reaction terminates, adds in 8000ml water, below 30 DEG C, drip about 760 ~ 780ml concentrated hydrochloric acid, drip off stirring 2 hours.Suction filtration is also washed, and obtains khaki color solid 2-(the chloro-2-nitrophenyl of 4-) dimethyl malonate, dries 346g, content: 93.4% yield: 92.2%, without the need to purifying, be directly used in the next step.
(3) preparation of the chloro-2-nitrophenyl-acetic acid of 4-
5000ml there-necked flask adds 830ml acetic acid, 2-(the chloro-2-nitrophenyl of the 4-) dimethyl malonate of 356g is added under stirring, slowly add 1850ml concentrated hydrochloric acid again, finish and be slowly warming up to 90-100 DEG C, insulation reaction 5 ~ 7 hours, less than 30 DEG C are cooled to after having reacted, reaction solution is poured in 4600g cold water, stirs and be cooled to less than 15 DEG C, suction filtration also uses 600ml water washing, obtain khaki color solid, i.e. 4-chlorine 2--nitrophenyl-acetic acid.Dry 316.6g content: 98% yield: 98.5%
(4) preparation of 6-chlorine oxindole
3000ml there-necked flask adds 700ml acetic acid and 700ml methyl alcohol, and add the chloro-2-nitrophenyl-acetic acid of 4-262.5 grams under stirring, heat temperature raising 50 ~ 55 DEG C, add-on is 150g iron powder in batches, finishes, and is slowly warming up to backflow, insulation reaction 2-4 hour.React complete, be cooled to less than 30 DEG C, pour in 13L cold water, add 1.3Lml concentrated hydrochloric acid, stir 3 hours, lower the temperature less than 15 DEG C, suction filtration is also washed with water to neutrality, obtain khaki color solid, i.e. 6-chlorine oxindole, dry 195g content: 98.8% yield: 89.4%.Gained solids with methanol recrystallization, activated carbon decolorizing, crystallisation by cooling, filters, dry 145g product 6-chlorine oxindole, content 99.5%.
About the related description of patent application of the present invention and detected result as follows:
One .2-(the chloro-2-nitrophenyl of 4-) malonic acid dimethyl Lipase absobed:
1. former synthesis technique one:
Present invention process adopts sodium hydride/DMSO system, 100 DEG C of reactions, and yield is 84%, and due to system NaH, reaction is violent, wayward, and due to sharply heat release and the easy blast on fire of NaH chance water, be unfavorable for suitability for industrialized production, yield is not high yet.
2. former synthesis technique two:
This synthesis technique about 2-(the chloro-2-nitrophenyl of 4-) dimethyl malonate is: adopt 25% sodium methylate/methyl alcohol, DMF system, temperature of reaction 95 DEG C, yield 79%, yield is low, and due to the easy moisture absorption of sodium methylate, after the moisture absorption, catalytic activity reduces greatly, and product yield is lower, the freshly prepd sodium methylate of general needs does, and control of industrialization is also more difficult.
3. technique after improving:
Improve after salt of wormwood/DMSO system, 85-95 DEG C of reaction, yield can reach 93-95%, and yield is significantly improved, and reaction temperature and, be easy to control, be conducive to realizing industrialization.
Two. synthesize 6-chlorine oxindole by the chloro-2-nitrophenyl-acetic acid of 4-:
1. former synthesis technique one:
Adopt metallic tin powder and methyl alcohol at room temperature to react, process recovery ratio: 79%, yield is low, and glass putty price is higher, and cost also increases accordingly;
2. former synthesis technique two:
This technique adopts 5%Pt/C shortening, 65-105 DEG C, 10kgf/cm
2, yield: 71%, need autoclave equipment, processing safety is low, and operation easier is comparatively large, and yield is also on the low side.
3. technique after improving:
Present invention process adopt iron powder reducing, backflow insulation reaction, reaction temperature and, be easy to control, iron powder existing market valency 12 yuan/kg, and glass putty 165 yuan/kg, reduce the material cost of reaction, and yield can reach 93%.
Claims (6)
1. a synthetic method for 6-chlorine oxindole, is characterized in that: step is as follows:
(1) by santochlor nitrated preparation 2,5-dichloronitrobenzene:
Santochlor is dropped in nitric-sulfuric acid, insulation reaction 2-6h under 50-100 DEG C of condition, reaction terminates rear cooling 50-70 DEG C, adds in the frozen water of 0 DEG C by reaction solution, and stir hydrolysis, material additional proportion is reaction solution: the mass ratio of water is 1:0.5-1, filter, obtain 2,5-dichloronitrobenzene solid, this solids wash to neutrality is obtained khaki color solid, 2, the 5-dichloronitrobenzenes that content is greater than 99%;
Wherein, the weight ratio of described santochlor and nitric-sulfuric acid is: 1: 2-5; Described nitric-sulfuric acid is the mixture of the vitriol oil and concentrated nitric acid, the vitriol oil: the weight ratio of concentrated nitric acid is 1: 0.2-0.5;
(2) prepare 2-(the chloro-2-nitrophenyl of 4-) dimethyl malonate by 2,5-dichloronitrobenzene:
Add dimethyl sulfoxide (DMSO) and dimethyl malonate, 2 are added under stirring, 5-dichloronitrobenzene and salt of wormwood, heat temperature raising, 50-100 DEG C of insulation reaction 3-10h, 10-50 DEG C is cooled to after having reacted, reaction solution is added to the water, adding the water yield is: 2, 5-dichloronitrobenzene: the mass ratio of water is 1: 20-35, mass concentration 25-30% hydrochloric acid is added again below 30 DEG C, hydrochloric acid consumption is: 2, 5-dichloronitrobenzene: the mass ratio of hydrochloric acid is 1: 3-5, stir 1-3h, filter, be washed to neutrality, obtaining khaki color solid is 2-(the chloro-2-nitrophenyl of 4-) dimethyl malonate,
Wherein, the weight ratio of 2,5-dichloronitrobenzene and dimethyl malonate and salt of wormwood insulation reaction in dimethyl sulfoxide (DMSO) is: 2,5-dichloronitrobenzene: dimethyl malonate: salt of wormwood=1: 1-3: 1-6; Solvent load is: 2,5-dichloronitrobenzene: the weight ratio of dimethyl sulfoxide (DMSO) is 1: 6-20;
(3) by 2-(4-chloro-2-nitrophenyl) the chloro-2-nitrophenyl-acetic acid of malonic acid dimethyl Lipase absobed 4-:
2-(the chloro-2-nitrophenyl of 4-) dimethyl malonate is added in acetic acid, add mass concentration 20-37% hydrochloric acid again, be heated to 50-100 DEG C, insulated and stirred 3-6h, less than 30 DEG C are cooled to after having reacted, reaction solution being poured in cold water, stirs and be cooled to less than 15 DEG C, filter, being washed to neutral khaki color solid to be the chloro-2-nitrophenyl-acetic acid of 4-;
Wherein, 2-(the chloro-2-nitrophenyl of 4-) dimethyl malonate insulation reaction in acetic acid and hydrochloric acid, its weight ratio is 2-(the chloro-2-nitrophenyl of 4-) dimethyl malonate: acetic acid: hydrochloric acid=1: 1-6: 4-9;
(4) prepare 6-chlorine oxindole by the chloro-2-nitrophenyl-acetic acid of 4-:
The chloro-2-nitrophenyl-acetic acid of 4-is added in acetic acid and methyl alcohol, heat temperature raising 50 ~ 55 DEG C, add iron powder, slowly be warming up to backflow, backflow insulation reaction 2-5h, after reaction terminates, be cooled to less than 30 DEG C, be added to the water to reaction solution, adding the water yield is: the chloro-2-nitrophenyl-acetic acid of 4-: the mass ratio of water is 1: 30-60, add mass concentration 25-30% hydrochloric acid, hydrochloric acid consumption is: the chloro-2-nitrophenyl-acetic acid of 4-: the mass ratio of hydrochloric acid is 1: 3-6, stir 3-4h, lower the temperature less than 15 DEG C, filter, being washed to neutrality, to obtain khaki color solid be 6-chlorine oxindole, the final product being greater than 99% is obtained again by recrystallizing methanol,
Wherein, the chloro-2-nitrophenyl-acetic acid of 4-reacts with iron powder in mixed solvent, and its weight ratio is the chloro-2-nitrophenyl-acetic acid of 4-: iron powder: acetic acid: methyl alcohol=1: 0.5-2: 1-7: 2-5.
2. the synthetic method of 6-chlorine oxindole according to claim 1, is characterized in that: described step (1) middle nitric acid is concentrated nitric acid or nitrosonitric acid.
3. the synthetic method of 6-chlorine oxindole according to claim 1, is characterized in that: the described step (1) middle dichlorobenzene insulation reaction temperature dropped in nitric-sulfuric acid is 70-90 DEG C.
4. the synthetic method of 6-chlorine oxindole according to claim 1, is characterized in that: described in be filtered into suction filtration.
5. the synthetic method of 6-chlorine oxindole according to claim 1, is characterized in that: described step (1) in be hydrolyzed in reaction solution, to add cold water after stir 1 hour.
6. the synthetic method of the 6-chlorine oxindole according to any one of claim 1 to 5, it is characterized in that: described step (1) in santochlor dropped in nitric-sulfuric acid be specially: get the part vitriol oil, add santochlor under stirring, add under water cooling in the nitric-sulfuric acid be made up of the residue vitriol oil and nitric acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510145735.8A CN104744338A (en) | 2015-03-31 | 2015-03-31 | Method for synthesizing 6-chlorhydroxyl indole |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510145735.8A CN104744338A (en) | 2015-03-31 | 2015-03-31 | Method for synthesizing 6-chlorhydroxyl indole |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104744338A true CN104744338A (en) | 2015-07-01 |
Family
ID=53584691
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510145735.8A Pending CN104744338A (en) | 2015-03-31 | 2015-03-31 | Method for synthesizing 6-chlorhydroxyl indole |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104744338A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105753765A (en) * | 2016-04-15 | 2016-07-13 | 浙江美诺华药物化学有限公司 | Preparation method of ziprasidone intermediate |
| CN108191633A (en) * | 2018-01-23 | 2018-06-22 | 辽宁东科药业有限公司 | A kind of method for synthesizing homoanisic acid |
| CN113004142A (en) * | 2020-12-28 | 2021-06-22 | 台州达辰药业有限公司 | Novel preparation method of 2,4, 5-trifluoro-phenylacetic acid |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4690943A (en) * | 1984-09-19 | 1987-09-01 | Pfizer Inc. | Analgesic and antiinflammatory 1,3-diacyl-2-oxindole compounds |
| US5679799A (en) * | 1994-11-04 | 1997-10-21 | K-I Chemical Industry Co., Ltd. | Method for producing oxyindoles |
| CN1747950A (en) * | 2002-12-19 | 2006-03-15 | 美国辉瑞有限公司 | 2-(1h-indazole-6-ylamino)-benzamide compounds as protein kinases inhibitors useful for the treatment of ophthalmic diseases |
| CN102241635A (en) * | 2011-04-28 | 2011-11-16 | 江苏宝众宝达药业有限公司 | Preparation method for anthelmintic benzimidazole fenbendazole |
| WO2012020424A1 (en) * | 2010-08-12 | 2012-02-16 | Arch Pharmalabs Limited | A short process for the preparation of ziprasidone and intermediates thereof |
| WO2013093928A1 (en) * | 2011-12-20 | 2013-06-27 | Arch Pharmalabs Limited | An improved process for preparing 2-oxindoles of formula i, a key raw material for making pharmaceutical drugs and intermediates thereof |
-
2015
- 2015-03-31 CN CN201510145735.8A patent/CN104744338A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4690943A (en) * | 1984-09-19 | 1987-09-01 | Pfizer Inc. | Analgesic and antiinflammatory 1,3-diacyl-2-oxindole compounds |
| US5679799A (en) * | 1994-11-04 | 1997-10-21 | K-I Chemical Industry Co., Ltd. | Method for producing oxyindoles |
| CN1747950A (en) * | 2002-12-19 | 2006-03-15 | 美国辉瑞有限公司 | 2-(1h-indazole-6-ylamino)-benzamide compounds as protein kinases inhibitors useful for the treatment of ophthalmic diseases |
| WO2012020424A1 (en) * | 2010-08-12 | 2012-02-16 | Arch Pharmalabs Limited | A short process for the preparation of ziprasidone and intermediates thereof |
| CN102241635A (en) * | 2011-04-28 | 2011-11-16 | 江苏宝众宝达药业有限公司 | Preparation method for anthelmintic benzimidazole fenbendazole |
| WO2013093928A1 (en) * | 2011-12-20 | 2013-06-27 | Arch Pharmalabs Limited | An improved process for preparing 2-oxindoles of formula i, a key raw material for making pharmaceutical drugs and intermediates thereof |
Non-Patent Citations (3)
| Title |
|---|
| ERICA A.KRAYNACK,等: "An improved procedure for the regiospecific synthesis of electron deficient 4-and 6-substituted isatins", 《TETRAHEDRON LETTERS》 * |
| 徐大国: "5-(2-氯乙基)-6-氯-1,3-二氢-吲哚酮的合成", 《浙江化工》 * |
| 郭希,等: "5-(2-氯乙酰基)-6-氯-吲哚酮的合成", 《武汉工程大学学报》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105753765A (en) * | 2016-04-15 | 2016-07-13 | 浙江美诺华药物化学有限公司 | Preparation method of ziprasidone intermediate |
| CN108191633A (en) * | 2018-01-23 | 2018-06-22 | 辽宁东科药业有限公司 | A kind of method for synthesizing homoanisic acid |
| CN113004142A (en) * | 2020-12-28 | 2021-06-22 | 台州达辰药业有限公司 | Novel preparation method of 2,4, 5-trifluoro-phenylacetic acid |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103626774B (en) | Yi Lu is for the preparation method of Buddhist nun | |
| CN105111205B (en) | A kind of preparation method of Pa Boxini | |
| CN104744338A (en) | Method for synthesizing 6-chlorhydroxyl indole | |
| CN102311355A (en) | Preparation method of rofecoxib | |
| US11987549B2 (en) | Preparation method of rhodium octanoate dimer | |
| CN105859615A (en) | Novel preparation method and novel intermediate of dequalinium chloride | |
| CN108715574A (en) | A method of synthesis '-biphenyl diphenol | |
| CN102993237A (en) | Aqueous-phase synthesis method of chlorpyrifos by using trichloro-acetic chloride as initial material | |
| CN103059098B (en) | Preparation method of dutasteride | |
| CN101157605B (en) | Method for producing acetylacetone copper | |
| CN104650093A (en) | Synthesis method of sildenafil analog | |
| CN112592364A (en) | Kribotron intermediate, preparation method and application thereof in preparation of Kribotron | |
| CN106349229B (en) | The preparation method and midbody compound of Lei Dipawei intermediates | |
| CN106905234B (en) | A method of the synthesis chloro- 6- amino -7- ethoxyquinoline of linatinib intermediate 3- cyano -4- | |
| CN105348323A (en) | Chlorpyrifos aqueous-phase synthesizing method with trichloro-acetic chloride as primary raw material | |
| CN108017612A (en) | A kind of preparation method of canagliflozin intermediate | |
| CN107118088A (en) | A kind of preparation method of m-hydroxy acetophenone | |
| CN101579641B (en) | Method for preparing alkylbenzene directional ring chlorination complex catalyst | |
| CN109761914B (en) | Method for preparing 5-trifluoromethyl uracil | |
| CN110041274B (en) | Method for preparing 5-fluoroalkyl triazole compound by air oxidation multi-component one-pot method | |
| CN106117118A (en) | A kind of preparation technology of bupivacaine hydrochloride | |
| CN103012292B (en) | Synthetic method of dibenzanthracene [b,f][1,2] diazocine | |
| CN104311377A (en) | Synthesis method of biphenyl compounds | |
| CN102432524A (en) | Method for preparing indole-2-carboxylic acid | |
| CN102382053B (en) | A kind of method preparing tolvaptan intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20150701 |