CN101544589B - Preparation for medicinal intermediate 6-chloro-5-fluroindole for synthesizing anti-cancer medicament - Google Patents
Preparation for medicinal intermediate 6-chloro-5-fluroindole for synthesizing anti-cancer medicament Download PDFInfo
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- CN101544589B CN101544589B CN2009100508662A CN200910050866A CN101544589B CN 101544589 B CN101544589 B CN 101544589B CN 2009100508662 A CN2009100508662 A CN 2009100508662A CN 200910050866 A CN200910050866 A CN 200910050866A CN 101544589 B CN101544589 B CN 101544589B
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Abstract
The present invention relates to preparation for a medicinal intermediate 6-chloro-5-fluroindole for synthesizing an anti-cancer medicament, which comprises the following steps that: firstly, 3-fluro-4-aminotoluene reacts in a concentrated sulfuric acid system, the pH value is adjusted to be neutral after the reaction, and the mixture is filtered to obtain 3-fluro-4-amino-6-nitrotoluene; secondly, a sodium nitrite solution and cuprous chloride are added in the concentrated sulfuric acid system, and the mixture is diluted by clear water to obtain 3-fluro-4-chloro-6-nitrotoluene; thirdly, the 3-fluro-4-chloro-6-nitrotoluene and N, N-dimethyl formamide dimethylacetal react in a molecular sieve drying DMF system to obtain 2-(2-(N,N-dimethylamino) ethylene)-4-fluro-5-chloro-nitrobenzene; and finally, iron powder is added into an acetic acid system, and after the reaction, the mixture is recrystallized by using a mixed system containing petroleum ether to obtain the white 6-chloro-5-fluroindole. The method has the advantages of simple operation, environmental friendliness, high purity and low cost, and is suitable for industrialized production.
Description
Technical field
The invention belongs to medicine intermediate and contain the preparation field of fluoro indole, particularly relate to a kind of preparation that is used for the medicine intermediate 6-chloro-5-fluoro indole of synthetic cancer therapy drug.
Background technology
At present, because 6-chloro-5-fluoro indole is the important intermediate that preparation is used for anticancer newtype drug, several big pharmacy corporations all have the development project of the anti-carcinoma of the pancreas new drug of treatment, much entered clinical stage, therefore, the demand of this intermediate is vigorous gradually, has than the large outlet potentiality of earning foreign exchange.As prepare GlaxoSmithKline PLC company new drug " GSK-3 β inhibitor ", and use this intermediate, can obtain final bulk drug through simple reaction, can effectively simplify drug manufacture technology.
But nowadays known many methods for preparing 6-chloro-5-fluoro indole, 1:(Tetrahedron Letters Volume 43, Issue 42,14October 2002, Pages 7581-7583) 2:(Bioorganic ﹠amp; Medicinal Chemistry Letters Volume 14, Issue 9,3May 2004, Pages 2367-2370) all mention related methods of synthesis in the document, but synthesis technique can only realize that all the laboratory restrains rank in a small amount and synthesizes, technology is difficult to amplify, the aftertreatment complexity, productive rate is not high, pollutes greatlyyer, and industrialization value is little.
Summary of the invention
Technical problem to be solved by this invention provides a kind of preparation that is used for the medicine intermediate 6-chloro-5-fluoro indole of synthetic cancer therapy drug, and preparation technology of the present invention has simple to operate, and is environmentally friendly, productive rate height, low cost and other advantages; The pure product 6-of the target compound that this method obtains chloro-5-fluoro indole purity reaches more than 97%, and overall yield is more than 50%.
Reaction equation of the present invention is as follows:
A kind of preparation that is used for the medicine intermediate 6-chloro-5-fluoro indole of synthetic cancer therapy drug of the present invention comprises:
(1) in mass concentration 98% vitriol oil, drips 3-fluoro-4-phenylmethylamine to the dissolving clarification, be cooled to-10～-5 ℃, adding mass concentration 65% concentrated nitric acid again mixes, mixed solution poured into be stirred to thawing in the ice bath, regulate pH to 6.8～7.2, again successively after filtration, dry, washing, in 35～45 ℃ of down dry 18～22h, faint yellow solid 3-fluoro-4-amino-6-nitrotoluene;
(2) 3-fluoro-4-amino-6-nitrotoluene is mixed with the concentrated hydrochloric acid of mass concentration 36.5%, stirring and dissolving, be cooled to-5～0 ℃, adding concentration is the aqueous solution of the Sodium Nitrite of 160～180g/L, then reaction solution is poured in the mixed system that contains CuCl and mass concentration 36.5% concentrated hydrochloric acid, stir thin up, more after filtration, dry, washing, in 20 ℃ of dry pale solid 3-fluoro-4-chloro-6 nitrotoluenes;
(3) with 3-fluoro-4-chloro-6 nitrotoluenes and N, dinethylformamide dimethylacetal DMFDMA is dissolved in the DMF system of molecular sieve drying, intensification is heated to 140 ℃, stir 3h, be cooled to room temperature, filter the back and in filtrate, add water and be stirred to red solid and separate out, dry again after filtration,, wash, in 30 ℃ of dry 24h, get red solid 2-(2-(N, N-dimethylamino) vinyl)-4-fluoro-5-chloro-oil of mirbane;
(4) with 2-(2-(N, the N-dimethylamino) vinyl)-Glacial acetic acid of 4-fluoro-5-chloro-oil of mirbane, reduced iron powder and mass concentration 99% is by the mixed of 3～4kg: 1～3kg: 25L, is heated to 60 ℃ and stirs 8h, treat that red raw material disappears after, be cooled to room temperature, after filtration and underpressure distillation, resistates is dissolved in the methylene dichloride clear water extracting and washing, steaming vibrating dichloromethane, add toluene again and be heated to 80 ℃, behind the sherwood oil recrystallization, promptly get white crystal 6-chloro-5-fluoro indole.
The ratio of the vitriol oil in the described step (1) and 3-fluoro-4-phenylmethylamine is 5～7L: 1kg, and the add-on of concentrated nitric acid is 0.5～1: 1 with respect to the mass ratio of 3-fluoro-4-phenylmethylamine;
The ratio of concentrated hydrochloric acid in the described step (2) and 3-fluoro-4-phenylmethylamine is 10～12L: 1kg; The mass ratio of Sodium Nitrite and 3-fluoro-4-amino-6-nitrotoluene is 1: 1.5～3;
N in the described step (3), dinethylformamide dimethylacetal DMFDMA are through 4A activated molecular sieve exsiccant;
3-fluoro-4-chloro-6 nitrotoluenes and N in the described step (3), the ratio of dinethylformamide dimethylacetal DMFDMA is 2kg: 2～3L, the ratio of the DMF of 3-fluoro-4-chloro-6 nitrotoluenes and molecular sieve drying is 2kg: 8～12L;
The consumption of the toluene in the described step (4) is 1L: 1～1.5kg with respect to the volume mass ratio of 2-(2-(N, N-dimethylamino) vinyl)-4-fluoro-5-chloro-oil of mirbane; The consumption of sherwood oil is 6L: 1～1.5kg with respect to the volume mass ratio of 2-(2-(N, N-dimethylamino) vinyl)-4-fluoro-5-chloro-oil of mirbane.
The anticancer of the present invention preparation can be applicable to field of biological pharmacy with Medicine intermediate one 6-chloro-5-fluoro indole, is mainly used in to make to treat anticancer class medicine-as anti-carcinoma of the pancreas medicine.
Of the present invention the first step product 3-fluoro-4-amino-6-nitro first reaction yield is greater than 90%, and product purity is more than 98%, and outward appearance is a faint yellow solid; The second step product 3-fluoro-4-chloro-, 6 nitrotoluene reaction yields are greater than 80%, and product purity is more than 95%, and outward appearance is the class pale solid; (2-(N, N-dimethylamino) vinyl)-4-fluoro-5-chloro-oil of mirbane productive rate is greater than 80% for the 3rd step product 2-, and product purity is more than 90%, and outward appearance is a red solid; The 4th step product 6-chloro-5-fluoro indole reaction yield is greater than 60%, and product purity is more than 97%, and outward appearance is a white solid.
Beneficial effect
(1) preparation technology of the present invention have simple to operate, environmentally friendly, productive rate height, low cost and other advantages;
(2) the pure product 6-of the target compound chloro-5-fluoro indole purity that obtains of this method reaches more than 97%, and overall yield is more than 50%.
Embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after the content of having read the present invention's instruction, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
Embodiment 1
The first step reaction: preparation A2 (3-fluoro-4-amino-6-nitrotoluene)
In 10 liters mechanical stirring glass reaction still, add 6 liters of dense ℃ of 98% vitriol oils, drip 1 kilogram of A1, dropwised in 1 hour, after the question response mixed solution dissolving clarification, reaction system cools to subzero to 10 ℃, keep following 10 ℃-subzero 5 ℃ of zero temperature, drip 65% dense ℃ of concentrated nitric acid of 760 grams, dropwised in 3 hours, stirred then 30 minutes; Reaction soln poured in 10 kilograms of rubble ices stir, after treating that ice melts fully, with aqueous sodium hydroxide solution the reaction solution pH value is adjusted to 7, keep temperature to be lower than 30 ℃ during adjusting, continue to stir 30 minutes, filter by the centrifuge apparatus that filter cloth is housed, drying obtains A2 (3-fluoro-4-amino-6-nitrotoluene) crude product, after using 10 liters of clear water washed twice then, dry moisture with centrifuge apparatus once more, obtain containing the small amount of moisture product, 40 ℃ of forced air dryings 20 hours, obtain dry faint yellow solid product 3-fluoro-4-amino-1.30 kilograms of 6-nitrotoluenes (purity is greater than 97%, and productive rate is greater than 90%).
Second step reaction: preparation A3 (3-fluoro-4-chloro-6 nitrotoluenes)
In 10 liters mechanical stirring glass reaction still, the analytical pure concentrated hydrochloric acid that adds 6 liter of 36.5% concentration, add 500 gram A2 (3-fluoro-4-amino-6-nitrotoluene) in batches, treat that A2 all dissolves, after the reaction solution clarification, cool to subzero 5 ℃, keep temperature to be lower than 0 ℃, drip 1.5 premium on currency solution of 250 gram Sodium Nitrites, dropwised in 2 hours, continue to stir 30 minutes.Then reaction solution is poured in the concentrated hydrochloric acid of 36.5% concentration that is added with 480 gram cuprous chlorides.Keep stirring, treat the bubble completely dissolve, add 20 liters of clear water diluting reaction systems, stirred 2 hours, filter drying by the whizzer that filter cloth is housed and obtain pale solid, solid dries with 10 liters of washed twice of clear water, dries at 20 ℃.Obtain 450 gram canescence product A, 3 (productive rate is greater than 80% for 3-fluoro-4-chloro-6 nitrotoluenes, purity＞95%) at last.
Acid filtrate is regulated PH by sodium hydroxide solution and is equaled 7, after the clear water dilution reaches sewage drainage standard, and discharging.
Three-step reaction: preparation A4 (2-(2-(N, N-dimethylamino) vinyl)-4-fluoro-5-chloro-oil of mirbane)
In 50L mechanical stirring enamel reactor, add dry 24 hours DMF (N of 4A activated molecular sieve, dinethylformamide) solvent 10L, add 2 kilograms of A3 (3-fluoro-4-chloro-6 nitrotoluenes) and 2.5 liters of 4A activated molecular sieve exsiccant N then, dinethylformamide dimethylacetal (DMFDMA) in batches.Add the back and stir the heating that heats up, and in system, add 5 kilograms of 4A activated molecular sieves, continue to heat to 140 ℃, stirred 3 hours.Cool to room temperature, cross and filter out after the molecular sieve, add 50 liters of clear water in reaction filtrate, stirred 2 hours, a large amount of red solid are separated out, obtain red solid by being with filter cloth whizzer filtration unit filtration drying separation, with 20 liters of washed twice of clear water, obtain moisture red product after the drying, 30 ℃ of air blast oven dry 24 hours, obtain 2.4 kilograms of red A4 (2-(2-(N, N-dimethylamino) vinyl)-4-fluoro-5-chloro-oil of mirbane).H-NMR verifies structure, and purity is greater than 90%, and productive rate is greater than 80%
Four-step reaction: preparation 6-chloro-5-fluoro indole
In 50L mechanical stirring enamel reactor, add 3.3 kilograms of raw material A 4 (2-(2-(N in batches, the N-dimethylamino) vinyl)-4-fluoro-5-chloro-oil of mirbane), 25 liters in 99% purity Glacial acetic acid, 2 kilograms of reduced iron powders, be heated to 60 ℃ and stirred 8 hours, red raw material disappearance postcooling arrives room temperature, crosses by filter cloth and filters out iron powder, acetic acid is removed in the filtrate decompression distillation, distillation residue are dissolved in the 20L methylene dichloride, after 10 liters of clear water extracting and washing 2 times, the dichloromethane layer evaporate to dryness are obtained the brown crude product, crude product joins in the 3L toluene, be heated to 80 ℃ of dissolvings fully, add 18 liters of sherwood oils then, keep stirring 20 hours, after naturally cooling to room temperature, 1.2 kilograms of the white crystal 6-chloro-5-fluoro indoles (HNMR confirms structure, HPLC purity＞97%, productive rate＞50%) that filtration obtains separating out.
Claims (6)
1. preparation that is used for the medicine intermediate 6-chloro-5-fluoro indole of synthetic cancer therapy drug comprises:
(1) in mass concentration 98% vitriol oil, drips 3-fluoro-4-phenylmethylamine to the dissolving clarification, be cooled to-10～-5 ℃, adding mass concentration 65% concentrated nitric acid again mixes, mixed solution poured into be stirred to thawing in the ice bath, regulate pH value to 6.8～7.2, after filtration, dry, washing, in 35～45 ℃ of down dry 18～22h, faint yellow solid 3-fluoro-4-amino-6-nitrotoluene;
(2) 3-fluoro-4-amino-6-nitrotoluene is mixed with the concentrated hydrochloric acid of mass concentration 36.5%, stirring and dissolving, be cooled to-5～0 ℃, adding concentration is the aqueous solution of the Sodium Nitrite of 160～180g/L, then reaction solution is poured in the mixed system that contains CuCl and mass concentration 36.5% concentrated hydrochloric acid, stir thin up, after filtration, dry, washing, in 20 ℃ of dry pale solid 3-fluoro-4-chloro-6 nitrotoluenes;
(3) with 3-fluoro-4-chloro-6 nitrotoluenes and N, dinethylformamide dimethylacetal DMFDMA is dissolved in the DMF system of 4A molecular sieve drying, intensification is heated to 140 ℃, stir 3h, be cooled to room temperature, filter the back and in filtrate, add water and be stirred to red solid and separate out, dry again after filtration,, wash, in 30 ℃ of dry 24h, get red solid 2-(2-(N, N-dimethylamino) vinyl)-4-fluoro-5-chloro-oil of mirbane; Wherein the 4A molecular sieve is retained in the reaction system;
(4) with 2-(2-(N, the N-dimethylamino) vinyl)-Glacial acetic acid of 4-fluoro-5-chloro-oil of mirbane, reduced iron powder and mass concentration 99% is by the mixed of 3～4kg: 1～3kg: 25L, is heated to 60 ℃ and stirs 8h, treat that red raw material disappears after, be cooled to room temperature, after filtration and underpressure distillation, resistates is dissolved in the methylene dichloride clear water extracting and washing, steaming vibrating dichloromethane, add toluene again and be heated to 80 ℃, behind the sherwood oil recrystallization, promptly get white crystal 6-chloro-5-fluoro indole.
2. a kind of preparation that is used for the medicine intermediate 6-chloro-5-fluoro indole of synthetic cancer therapy drug according to claim 1, it is characterized in that: the ratio of the vitriol oil in the described step (1) and 3-fluoro-4-phenylmethylamine is 5～7L: 1kg, and the add-on of concentrated nitric acid is 0.5～1: 1 with respect to the mass ratio of 3-fluoro-4-phenylmethylamine.
3. a kind of preparation that is used for the medicine intermediate 6-chloro-5-fluoro indole of synthetic cancer therapy drug according to claim 1, it is characterized in that: the ratio of concentrated hydrochloric acid in the described step (2) and 3-fluoro-4-phenylmethylamine is 10～12L: 1kg; The mass ratio of Sodium Nitrite and 3-fluoro-4-amino-6-nitrotoluene is 1: 1.5～3.
4. a kind of preparation that is used for the medicine intermediate 6-chloro-5-fluoro indole of synthetic cancer therapy drug according to claim 1 is characterized in that: the N in the described step (3), dinethylformamide dimethylacetal DMFDMA are through 4A activated molecular sieve exsiccant.
5. a kind of preparation that is used for the medicine intermediate 6-chloro-5-fluoro indole of synthetic cancer therapy drug according to claim 1, it is characterized in that: 3-fluoro-4-chloro-6 nitrotoluenes and N in the described step (3), the ratio of dinethylformamide dimethylacetal DMFDMA is 2kg: 2～3L, the ratio of the DMF of 3-fluoro-4-chloro-6 nitrotoluenes and 4A molecular sieve drying is 2kg: 8～12L, and the 4A molecular sieve is retained in the reaction system.
6. a kind of preparation that is used for the medicine intermediate 6-chloro-5-fluoro indole of synthetic cancer therapy drug according to claim 1, it is characterized in that: the consumption of the toluene in the described step (4) is 1L: 1～1.5kg with respect to the volume mass ratio of 2-(2-(N, N-dimethylamino) vinyl)-4-fluoro-5-chloro-oil of mirbane; The consumption of sherwood oil is 6L: 1～1.5kg with respect to the volume mass ratio of 2-(2-(N, N-dimethylamino) vinyl)-4-fluoro-5-chloro-oil of mirbane.
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| CN103420892A (en) * | 2012-05-18 | 2013-12-04 | 苏州爱斯鹏药物研发有限责任公司 | Preparation method of 4-fluoroindole |
| CN103450068B (en) * | 2012-05-27 | 2015-09-16 | 重庆常捷医药化工有限公司 | A kind of synthetic method of Ziprasidone intermediate |
| CN102746211B (en) * | 2012-06-27 | 2015-05-27 | 上海泰坦化学有限公司 | Method for preparing substituted indole-3-methanal compound |
| CN102924359B (en) * | 2012-10-30 | 2015-03-11 | 中国科学院烟台海岸带研究所 | Method for synthesizing substituted indole compounds through one-pot method |
| CN104557917A (en) * | 2014-12-12 | 2015-04-29 | 重庆博腾制药科技股份有限公司 | Preparation method of 5-halogenated azacycloindole |
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