CN106432040A - Environment-friendly synthesis method for medicine intermediate 5-bromoindole - Google Patents
Environment-friendly synthesis method for medicine intermediate 5-bromoindole Download PDFInfo
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- CN106432040A CN106432040A CN201610647909.5A CN201610647909A CN106432040A CN 106432040 A CN106432040 A CN 106432040A CN 201610647909 A CN201610647909 A CN 201610647909A CN 106432040 A CN106432040 A CN 106432040A
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- 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
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
Abstract
The invention relates to an environment-friendly synthesis method for a medicine intermediate 5-bromoindole. The method comprises the following steps: (1) subjecting indole to low-temperature low-pressure liquid-phase hydrogenation in the presence of a metal catalyst, so as to obtain indoline; (2) subjecting indoline to an action with an acetylation reagent, so as to produce N-acetylindoline; (3) subjecting N-acetylindoline to a clean bromination reaction, so as to produce N-acetyl-5-bromoindoline; (4) subjecting N-acetyl-5-bromoindoline to deacetylation under acidic conditions, so as to obtain 5-bromoindoline; and (5) subjecting 5-bromoindoline to oxidative dehydrogenation, thereby preparing the key medicine intermediate 5-bromoindole. Compared with the prior art, the method has the beneficial effects that a new environment-friendly synthesis process is developed, compared with the original process, bromo isomers of the 5-bromoindole product are effectively controlled, and the safety of medicine products can be higher; compared with the original acetic anhydride and bromine bromination process, the reaction conditions are mild, the environmental pollution is light, and the cost is low; and the equipment investment is small, the process is simple, the operation is easy, the equipment corrosion is low, and the process is more applicable to industrial production.
Description
Technical field
The present invention relates to the synthetic technology of 5- bromo indole and in particular to one kind by indole is hydrogenated, acylated, bromination, deacylation,
The synthetic method of 5- bromo indole is prepared in oxidative dehydrogenation.
Background technology
5- bromo indole, English name 5-Bromoindole, molecular formula is C8H6BrN, molecular weight is 196.05, is a kind of weight
The pharmaceutical-chemical intermediate wanted.
Benzazole compounds are widespread in nature, and on many phenyl ring, the indole containing substituent group all has physiology and lives
Property.5- substituent indole compound is a kind of important intermediate, has important application at aspects such as synthesis medicine, dyestuffs.Pine
Fruit parathyrine (melatonin, N-acetyl-5-methoxyuyptamine) also known as melatonin, mainly by 5- methoxy-Indole system
Take, it directly acts on hypothalamuses, there is hypnotic, endocrine regulation, the different physiological roles such as enhancing immunity.5- cyano group
The Benzazole compounds replacing are used for preparing vasoconstrictor to treat migraine, are also antidepressants hydrochloric acid vilazodone simultaneously
Important intermediate.Dyestuff containing 5- nitrine indole structure can be used for the dyeing of keratoprotein (hair, Pilus Caprae seu Oviss).5- furan or
The color aminated compoundss that thiophene replaces can be used for making 5-HTIDThe analeptic of receptor.5- miaow base indole is the inhibitor of thrombin, it
Can be reacted with 4- Phenylpiperidine by 5- cyanoindole -1- carboxylic acid and obtain.5- bromo indole is synthesis 5- cyanoindole, 5- methoxyl group Yin
The important intermediate of the compounds such as diindyl, it is very necessary for therefore the synthesis technique of 5- bromo indole being developed.
Both at home and abroad with regard to the report of 5- bromo indole synthesis, the technique that mainly adopts indole earlier sulfonation bromination again, this technique
Peracid is high-alkali, and product sulfur-bearing is high, and pollution environment is serious.Time-consuming for course of reaction, and mixing plant is had high demands, and yield is relatively
Low.This technique disadvantage is easily to introduce 7 bromo isomer in bromination process, and for pharmaceuticals industry, this is extremely dangerous
's.Domestic at present most employing the method produces 5- bromo indole, and production scale is little.In order to make full use of the indole in coal tar
Resource, one reaction condition of exploitation is gentle, environmental protection, reaction yield are high, the 5- bromo indole process route of low cost, has relatively
High strategic importance.
Content of the invention
It is an object of the invention to provide a kind of a kind of green synthesis method of medicine intermediate 5- bromo indole, with respect to original
Acetic anhydride and bromine bromination technique, reaction condition is gentle, and environmental pollution is little, low cost；Guarantee that medical product safety is higher.
The present invention employs the following technical solutions realization：
A kind of green synthesis method of medicine intermediate 5- bromo indole, first passes through low pressure liquid-phase hydrogenatin and destroys indole five-membered ring
Conjugation, protects to nitrogen, through green bromination technique, obtains high-purity bromination product, and through deprotection, prepared by oxidative dehydrogenation
Crucial medicine intermediate 5- bromo indole.
Using technical scheme：1. indoline is obtained through low-temp low-pressure liquid-phase hydrogenatin by indole；2. indoline and acylation
Reagent reacting synthesizes N- acetylindole quinoline；3. the cleaned bromination of N- acetylindole quinoline obtains N- acetyl group -5--bromo indole quinoline；
4. N- acetyl group -5--bromo indole quinoline deacylation in the presence of concentrated hydrochloric acid obtains 5--bromo indole quinoline；5. 5--bromo indole quinoline is through peroxidating
Dehydrogenation obtains crucial medicine intermediate 5- bromo indole.Concrete operation step is as follows：
Step 1：The synthesis of indoline
A) indole, metallic catalyst, organic solvent are added in autoclave and stir, indole, metallic catalyst, have
The mass ratio 1 of machine solvent:(0.05～0.50):(2～8) obtain reactant liquor A；
B), through nitrogen, after hydrogen is sufficiently displaced from, reactant liquor A is in H for autoclave2Pressure is 1～2.50Mpa, temperature 70～
150 DEG C of reactions；
C) hydrogenated mixture that step b) obtains is filtered, filter out catalyst, obtain liquor B；
D) after liquor B reclaims organic solvent, put in vacuum distillation kettle, collect 65 DEG C/1.33 × 10-3The fraction of Mpa,
Obtain indoline product.
Step 2：N- acetylindole quinoline synthesizes
A) indoline, halogenated hydrocarbon solvent are put in reaction bulb, obtain reactant mixture C；
B), to Deca acylating reagent in mixture C, after completion of dropping, monitor and disappear to raw material.Indoline, acylating reagent,
The mol ratio of halogenated hydrocarbon solvent is 1:(1～2):(1～20), 0～50 DEG C of reaction, obtain mixture D；
C) N- acetylindole quinoline product will after mixture D recycling design, be obtained；
Step 3：The synthesis of N- acetyl group -5--bromo indole quinoline
A) N- acetylindole quinoline, bromating agent, halogenated hydrocarbon solvent are put in reaction bulb, stir, N- acetyl group
Indoline, bromating agent, the mol ratio of halogenated hydrocarbon solvent are 1:(0.50～2):(2～20), obtain reactant mixture E；
B) reactant mixture E reacts at 0～45 DEG C, obtains mixture F；
C) the saturated aqueous solution neutralization of mixture F sodium sulfite, until redness is wholly absent in reactant liquor, saturation is sub-
The quality of sodium bisulfate and reactant liquor F are than for 1:(1～10), point liquid, obtain organic faciess G and aqueous phase H；
D) organic faciess G are washed, and the water yield is (1～5) with the mass ratio of organic faciess:1；
E), after the recovered solvent of organic faciess G that step (d) obtains, obtain N- acetyl group -5--bromo indole quinoline product；
Step 4：The synthesis of 5--bromo indole quinoline
A) N- acetyl group -5--bromo indole quinoline, concentrated hydrochloric acid, alcohols solvent are put in reaction bulb, stir, N- acetyl
Base -5--bromo indole quinoline, concentrated hydrochloric acid, the mol ratio of alcohols solvent are 1:(0.50～5)：(0.50～5), obtains reactant mixture I；
B) reactant mixture I, at 30～100 DEG C, reacts 4～8h, and chromatograph monitoring raw material disappears；
C) it is neutralized to pH=5～11 with aqueous slkali, the mass ratio of the concentrated hydrochloric acid in alkali and reactant liquor I is (1～5):1, alkali
The mass percent of solution is 5%～50%；
D) it is layered, obtain organic faciess J and aqueous phase K；
E) recycling design, obtains 5--bromo indole quinoline product.
Step 5:The synthesis of 5- bromo indole
A) 5--bromo indole quinoline, dehydrogenation, solvent are put in reaction bulb, stir, 5--bromo indole quinoline, dehydrogenation
Catalyst, the mass ratio of solvent are 1:(0.50～5):(1～10), obtains reactant mixture L；
B) at 40～150 DEG C, oxidizer flow rate is 100～400mL/min to reactant mixture L, reacts 7～40h, and chromatograph is supervised
Control raw material disappears；
C) filter, leach dehydrogenation, obtain organic layer M, recycling design, obtain 5- bromo indole product.
Course of reaction is as follows：
Metallic catalyst described in step 1 is palladium carbon, ruthenium charcoal, platinum charcoal, Raney's nickel and nickel/Al2O3One of；Have
Machine solvent is one of toluene, dimethylbenzene or its mixture.
Indole described in step 1, metallic catalyst, the mass ratio of organic solvent are 1:(0.05～0.50):(2～8)；
Reaction pressure is 1～2.50MPa；Reaction temperature is 70～150 DEG C.
Acylating reagent described in step 2 is one of acetic anhydride, chloroacetic chloride, propionyl chloride, and solvent is dichloromethane, trichlorine
A kind of or its mixture in methane, dichloroethanes, 1,2- dichloroethanes.
Indoline described in step 2, acylating reagent, the mol ratio of halogenated hydrocarbon solvent are 1:(1～2):(1～20), reaction
Temperature is 0～50 DEG C.
Bromating agent described in step 3 is DBDMH, NBS, hydrobromic acid/H2O2；Solvent be dichloromethane, chloroform,
One of dichloroethanes or 1,2- dichloroethanes or its mixture.
N- acetylindole quinoline described in step 3, bromating agent, the mol ratio of halogenated hydrocarbon solvent are 1:(0.50～2):(2
～20), reaction temperature is 0～45 DEG C.
Acid described in step 4 is hydrochloric acid, and solvent is one of methanol, ethanol or its mixture.
N- acetyl group -5--bromo indole quinoline described in step 4, concentrated hydrochloric acid, the mol ratio of alcohols solvent are 1:(0.50～
5)：(0.50～5), reaction temperature is 30～100 DEG C.
Oxidant described in step 5 is one of air, oxygen；Catalyst is activated carbon, Carbon foam and activated carbon
A kind of in fiber；Solvent is one of toluene, dimethylbenzene or its mixture.
5--bromo indole quinoline described in step 5, dehydrogenation, the mass ratio of solvent are 1:(0.50～5):(1～10),
Reaction temperature is 40～150 DEG C.
Compared with prior art, the invention has the beneficial effects as follows：
1) develop a new green synthesizing process, with respect to former technique, effective control 5- bromo indole product bromo isomer,
Guarantee that medical product safety is higher；
2) with respect to original acetic anhydride and bromine bromination technique, reaction condition is gentle, and environmental pollution is little, low cost.
3) equipment investment is little, it is easy to operation equipment corrosion is little, technique is more suitable for industrialized production to process is simple.
Instantiation mode
With reference to specific embodiment, the present invention is described in further details：
Following examples describe the present invention.These embodiments are only that preferred embodiment of the invention is entered
Row description, does not limit to the scope of the present invention.
A kind of green synthesis method of medicine intermediate 5- bromo indole, the technical scheme of employing：1. by indole through low temperature
Low pressure liquid-phase hydrogenatin obtains indoline；2. indoline and acylating reagent are synthesized N- acetylindole quinoline；3. N- acetyl group Yin
The cleaned bromination of diindyl quinoline obtains N- acetyl group -5--bromo indole quinoline；4. N- acetyl group -5--bromo indole quinoline is de- in the presence of concentrated hydrochloric acid
Acyl obtains 5--bromo indole quinoline；5. 5--bromo indole quinoline obtains crucial medicine intermediate 5- bromo indole through oxidative dehydrogenation.Concrete operations
Step is as follows：
Step 1：The synthesis of indoline
A) indole, metallic catalyst, organic solvent are added in autoclave and stir, indole, metallic catalyst, have
The mass ratio 1 of machine solvent:(0.05～0.50):(2～8) obtain reactant liquor A；
B), through nitrogen, after hydrogen is sufficiently displaced from, reactant liquor A is in H for autoclave2Pressure is 1～2.50Mpa, temperature 70～
150 DEG C of reactions；
C) hydrogenated mixture that step b) obtains is filtered, filter out catalyst, obtain liquor B；
D) after liquor B reclaims organic solvent, put in vacuum distillation kettle, collect 65 DEG C/1.33 × 10-3The fraction of Mpa,
Obtain indoline product.
Step 2：N- acetylindole quinoline synthesizes
A) indoline, halogenated hydrocarbon solvent are put in reaction bulb, obtain reactant mixture C；
B), to Deca acylating reagent in mixture C, after completion of dropping, monitor and disappear to raw material.Indoline, acylating reagent,
The mol ratio of halogenated hydrocarbon solvent is 1:(1～2):(1～20), 0～50 DEG C of reaction, obtain mixture D；
C) N- acetylindole quinoline product will after mixture D recycling design, be obtained；
Step 3：The synthesis of N- acetyl group -5--bromo indole quinoline
A) N- acetylindole quinoline, bromating agent, halogenated hydrocarbon solvent are put in reaction bulb, stir, N- acetyl group
Indoline, bromating agent, the mol ratio of halogenated hydrocarbon solvent are 1:(0.50～2):(2～20), obtain reactant mixture E；
B) reactant mixture E reacts at 0～45 DEG C, obtains mixture F；
C) the saturated aqueous solution neutralization of mixture F sodium sulfite, until redness is wholly absent in reactant liquor, saturation is sub-
The quality of sodium bisulfate and reactant liquor F are than for 1:(1～10), point liquid, obtain organic faciess G and aqueous phase H；
D) organic faciess G are washed, and the water yield is (1～5) with the mass ratio of organic faciess:1；
E), after the recovered solvent of organic faciess G that step (d) obtains, obtain N- acetyl group -5--bromo indole quinoline product；
Step 4：The synthesis of 5--bromo indole quinoline
A) N- acetyl group -5--bromo indole quinoline, concentrated hydrochloric acid, alcohols solvent are put in reaction bulb, stir, N- acetyl
Base -5--bromo indole quinoline, concentrated hydrochloric acid, the mol ratio of alcohols solvent are 1:(0.50～5)：(0.50～5), obtains reactant mixture I；
B) reactant mixture I, at 30～100 DEG C, reacts 4～8h, and chromatograph monitoring raw material disappears；
C) it is neutralized to pH=5～11 with aqueous slkali, the mass ratio of the concentrated hydrochloric acid in alkali and reactant liquor I is (1～5):1, alkali
The mass percent of solution is 5%～50%；
D) it is layered, obtain organic faciess J and aqueous phase K；
E) recycling design, obtains 5--bromo indole quinoline product.
Step 5:The synthesis of 5- bromo indole
A) 5--bromo indole quinoline, dehydrogenation, solvent are put in reaction bulb, stir, 5--bromo indole quinoline, dehydrogenation
Catalyst, the mass ratio of solvent are 1:(0.50～5):(1～10), obtains reactant mixture L；
B) at 40～150 DEG C, oxidizer flow rate is 100～400mL/min to reactant mixture L, reacts 7～40h, and chromatograph is supervised
Control raw material disappears；
C) filter, leach dehydrogenation, obtain organic layer M, recycling design, obtain 5- bromo indole product.
Course of reaction is as follows：
Metallic catalyst described in step 1 is palladium carbon, ruthenium charcoal, platinum charcoal, Raney's nickel and nickel/Al2O3One of；Have
Machine solvent is one of toluene, dimethylbenzene or its mixture.
Indole described in step 1, metallic catalyst, the mass ratio of organic solvent are 1:(0.05～0.50):(2～8)；
Reaction pressure is 1～2.50MPa；Reaction temperature is 70～150 DEG C.
Acylating reagent described in step 2 is one of acetic anhydride, chloroacetic chloride, propionyl chloride, and solvent is dichloromethane, trichlorine
A kind of or its mixture in methane, dichloroethanes, 1,2- dichloroethanes.
Indoline described in step 2, acylating reagent, the mol ratio of halogenated hydrocarbon solvent are 1:(1～2):(1～20), reaction
Temperature is 0～50 DEG C.
Bromating agent described in step 3 is DBDMH, NBS, hydrobromic acid/H2O2；Solvent be dichloromethane, chloroform,
One of dichloroethanes or 1,2- dichloroethanes or its mixture.
N- acetylindole quinoline described in step 3, bromating agent, the mol ratio of halogenated hydrocarbon solvent are 1:(0.50～2):(2
～20), reaction temperature is 0～45 DEG C.
Acid described in step 4 is hydrochloric acid, and solvent is one of methanol, ethanol or its mixture.
N- acetyl group -5--bromo indole quinoline described in step 4, concentrated hydrochloric acid, the mol ratio of alcohols solvent are 1:(0.50～
5)：(0.50～5), reaction temperature is 30～100 DEG C.
Oxidant described in step 5 is one of air, oxygen；Catalyst is activated carbon, Carbon foam and activated carbon
A kind of in fiber；Solvent is one of toluene, dimethylbenzene or its mixture.
5--bromo indole quinoline described in step 5, dehydrogenation, the mass ratio of solvent are 1:(0.50～5):(1～10),
Reaction temperature is 40～150 DEG C.
Example 1：
A kind of green synthesis method of medicine intermediate 5- bromo indole, the technical scheme of employing：1. by indole through low temperature
Low pressure liquid-phase hydrogenatin obtains indoline；2. indoline and acylating reagent are synthesized N- acetylindole quinoline；3. N- acetyl group Yin
The cleaned bromination of diindyl quinoline obtains N- acetyl group -5--bromo indole quinoline；4. N- acetyl group -5--bromo indole quinoline is de- in the presence of concentrated hydrochloric acid
Acyl obtains 5--bromo indole quinoline；5. 5--bromo indole quinoline obtains crucial medicine intermediate 5- bromo indole through oxidative dehydrogenation.Concrete operations
As follows：
(1) synthesis of indoline
A) indole 100g (0.85mol), palladium carbon catalyst 5g (10%w.t) dimethylbenzene 200g are added in autoclave and stir
Mix uniformly, obtain reactant liquor A；
B) autoclave is through nitrogen displacement 8 times, and after hydrogen exchange 4 times, in hydrogen 2Mpa, 130 DEG C of temperature is anti-for reactant liquor A
Should；
C) hydrogenated mixture that step b) obtains is filtered, leach catalyst, obtain liquor B；
D) after liquor B reclaims organic solvent, put in vacuum distillation kettle, collect 65 DEG C/1.33 × 10-3The fraction of Mpa,
Obtain indoline product 91.56g, yield 90.02%, product gas chromatographic purity >=96%.
(2) synthesis of N- acetylindole quinoline
A) indoline 16g (0.13mol), dichloromethane 130g are put in reaction bulb, obtain reactant mixture C；
B) to Deca acetic anhydride 43g (0.13mol) in mixture C, after completion of dropping, 35 DEG C of reactions, obtain mixture D；
C) mixture D is reclaimed after dichloromethane solvent, obtain N- acetylindole quinoline product 20.41g, yield
94.15%, product liquid chromatograph purity >=99%；
(3) synthesis of N- acetyl group -5--bromo indole quinoline
A) N- acetylindole quinoline 20.30g (0.13mol), DBDMH 18g (0.06mol), dichloromethane 260g are thrown
Enter in reaction bulb, stir, obtain reactant mixture E；
B) reactant mixture reacts at 35 DEG C, obtains mixture F；
C) mixture F is neutralized with the saturated aqueous solution of 65g sodium sulfite, until redness is wholly absent in reactant liquor, point
Liquid, obtains organic faciess G and aqueous phase H；
D) organic faciess G are washed, and the water yield is 300g；
E) after the organic faciess G recycling design that step (d) obtains, obtain N- acetyl group -5--bromo indole quinoline product 27.57g, receive
Rate 91.22%, product liquid chromatograph purity >=98%；
(4) synthesis of 5--bromo indole quinoline
A) N- acetyl group -5--bromo indole quinoline 38g (0.16mol), concentrated hydrochloric acid 31g, ethanol 41g are put in reaction bulb,
Stir, obtain reactant mixture I；
B) reactant mixture I, at 78 DEG C, reacts 4h, and chromatograph monitoring raw material disappears；
C) use the sodium hydroxide solution neutralization of 55g；
D) it is layered, obtain organic faciess J and aqueous phase K；
E) organic faciess J 445g chloroform extraction 3 times, merges organic layer, recycling design, obtains 5--bromo indole quinoline product
30.74g, yield 98.04%, content >=99%.
(5) 5- bromo indole synthesis
A) 30g (0.15mol) 5--bromo indole quinoline, 60g activated carbon fiber catalyst, 264g dimethylbenzene are put into reaction bulb
Interior, stir, obtain reactant mixture L；
B) at 100 DEG C, oxygen flow is 200mL/min to reactant mixture L, reacts 8h, chromatograph monitoring raw material disappears；
C) filter, leach activated carbon fiber catalyst, organic layer recycling design, obtain 5- bromo indole product 22.37g, receive
Rate 75.34%, content >=95%.
Example 2：
A kind of green synthesis method of medicine intermediate 5- bromo indole, the technical scheme of employing：1. by indole through low temperature
Low pressure liquid-phase hydrogenatin obtains indoline；2. indoline and acylating reagent are synthesized N- acetylindole quinoline；3. N- acetyl group Yin
The cleaned bromination of diindyl quinoline obtains N- acetyl group -5--bromo indole quinoline；4. N- acetyl group -5--bromo indole quinoline is de- in the presence of concentrated hydrochloric acid
Acyl obtains 5--bromo indole quinoline；5. 5--bromo indole quinoline obtains crucial medicine intermediate 5- bromo indole through oxidative dehydrogenation.Concrete operations
As follows：
(1) synthesis of indoline
A) indole 100g (0.85mol), palladium carbon catalyst 12g (10%w.t), toluene 180g are put in autoclave and stir
Mix uniformly, obtain reactant liquor A；
B) autoclave is through nitrogen displacement 8 times, and after hydrogen exchange 4 times, reactant liquor A is in hydrogen 2.20Mpa, 100 DEG C of temperature
Reaction；
C) hydrogenated mixture that step b) obtains is filtered, leach catalyst, obtain liquor B；
D) after liquor B reclaims toluene, put in vacuum distillation kettle, collect 65 DEG C/1.33 × 10-3The fraction of Mpa, obtains
Indoline product 93.92g, yield 92.34%, product gas chromatographic purity >=96%.
(2) synthesis of N- acetylindole quinoline
A) indoline 16g (0.13mol), 1,2- dichloroethanes 140g, 18.56g Anhydrous potassium carbonate are put into reaction bulb
Interior, obtain reactant mixture C；
B) mixture C is cooled to 0 DEG C, the Deca chloroacetic chloride 11g (0.16mol) in mixture C, 0 DEG C after completion of dropping
Reaction, obtains mixture D；
C) mixture D is reclaimed after 1,2- dichloroethanes, obtain N- acetylindole quinoline product 18.55g, yield
85.68%, product liquid chromatograph purity >=98%；
(3) synthesis of N- acetyl group -5--bromo indole quinoline
A) by N- acetylindole quinoline 65g (0.40mol), 540g 1,2- dichloroethanes are put in reaction bulb, and stirring is all
Even, obtain reactant mixture E；
B) reactant mixture E is cooled to 0～5 DEG C, Deca 76.80g (0.48mol) bromine, obtain mixture F；
C) mixture F is neutralized with the saturated aqueous solution of 75g sodium sulfite, until redness is wholly absent in reactant liquor, point
Liquid, obtains organic faciess G and aqueous phase H；
D) organic faciess G are washed, and the water yield is 400g；
E), after organic faciess G that step (d) obtains reclaim 1,2- dichloromethane, obtain N- acetyl group -5--bromo indole quinoline product
90.24, yield 93.14%, product liquid chromatograph purity >=98%；
(3) synthesis of 5--bromo indole quinoline
A) N- acetyl group -5--bromo indole quinoline 38g (0.16mol), concentrated hydrochloric acid 41g, methanol 50g are put in reaction bulb,
Stir, obtain reactant mixture I；
B) reactant mixture I is at 70 DEG C；
C) it is neutralized to the sodium hydroxide solution of 70g, the mass percent of sodium hydroxide solution is 30%；
D) it is layered, obtain organic faciess J and aqueous phase K；
E) organic faciess J are extracted 3 times with 397g dichloromethane, merge organic layer, reclaim dichloromethane solvent, obtain 5- bromine Yin
Diindyl quinoline product 28.32g, yield 90.32%, content >=99%.
(5) 5- bromo indole synthesis
A) 30g (0.15mol) 5--bromo indole quinoline, 50g Carbon foam, 250g toluene are put in reaction bulb, stir,
Obtain reactant mixture L；
B) at 70 DEG C, oxygen flow is 220mL/min to reactant mixture L, reacts 15h, chromatograph monitoring raw material disappears；
C) filter, leach Carbon foam, organic layer recycling design, obtain 5- bromo indole product 20.05g, yield 67.51%,
Content >=95%.
Example 3：
A kind of green synthesis method of medicine intermediate 5- bromo indole, the technical scheme of employing：1. by indole through low temperature
Low pressure liquid-phase hydrogenatin obtains indoline；2. indoline and acylating reagent are synthesized N- acetylindole quinoline；3. N- acetyl group Yin
The cleaned bromination of diindyl quinoline obtains N- acetyl group -5--bromo indole quinoline；4. N- acetyl group -5--bromo indole quinoline is de- in the presence of concentrated hydrochloric acid
Acyl obtains 5--bromo indole quinoline；5. 5--bromo indole quinoline obtains crucial medicine intermediate 5- bromo indole through oxidative dehydrogenation.Concrete operations
As follows：
(1) synthesis of indoline
A) by indole 100g (0.85mol), palladium carbon catalyst 10g (10%w.t), dimethylbenzene 150g is added in autoclave
Stir, obtain reactant liquor A；
B) autoclave is through nitrogen displacement 8 times, and after hydrogen exchange 4 times, in hydrogen 2Mpa, 120 DEG C of temperature is anti-for reactant liquor A
Should；
C) hydrogenated mixture that step b) obtains is filtered, leach catalyst, obtain liquor B；
D) liquor B is put in vacuum distillation bottle after reclaiming dimethylbenzene, collects 65 DEG C/1.33 × 10-3The fraction of Mpa, obtains
To indoline product 96.06g, yield 94.45%, product gas chromatographic purity >=96%.
(2) synthesis of N- acetylindole quinoline
A) indoline 16g (0.13mol), dichloromethane 130g are put in reaction bulb, obtain reactant mixture C；
B) to Deca acetic anhydride 15g (0.15mol) in mixture C, after completion of dropping, 50 DEG C of reactions, obtain mixture D；
C) mixture D is reclaimed after dichloromethane solvent, obtain N- acetylindole quinoline product 20.81g, yield
96.15%, product liquid chromatograph purity >=99%；
(3) synthesis of N- acetyl group -5--bromo indole quinoline
A) by N- acetylindole quinoline 23g (0.14mol), 48% hydrobromic acid 23.63g (0.14mol), dichloromethane 260g
Put in reaction bulb, stir, obtain reactant mixture E；
B) reactant mixture is cooled to 20 DEG C, the hydrogen peroxide reaction of Deca 15.87g30%, obtain mixture F；
C) mixture F is neutralized with the saturated aqueous solution of 60g sodium sulfite, until redness is wholly absent in reactant liquor, point
Liquid, obtains organic faciess G and aqueous phase H；
D) organic faciess G are washed, and the water yield is 200g；
E), after organic faciess G that step (d) obtains reclaim dichloromethane solvent, obtain N- acetyl group -5--bromo indole quinoline product
32.79g, yield 95.64%, product liquid chromatograph purity >=99%；
(3) synthesis of 5--bromo indole quinoline
A) N- acetyl group -5--bromo indole quinoline 38g (0.16mol), concentrated hydrochloric acid 41g, ethanol 50g are put in reaction bulb,
Stir, obtain reactant mixture I；
B) reactant mixture I is at 80 DEG C；
C) use the sodium hydroxide solution neutralization of 50g, the mass percent of sodium hydroxide solution is 40%；
D) it is layered, obtain organic faciess J and aqueous phase K；
E) organic faciess J are extracted 3 times with 400g dichloromethane, merge organic layer, reclaim dichloromethane solvent, obtain 5- bromine Yin
Diindyl quinoline product 29.50g, yield 94.10%, content >=99%.
(5) 5- bromo indole synthesis
A) 30g (0.15mol) 5--bromo indole quinoline, 60g activated carbon, 264g dimethylbenzene are put in reaction bulb, stirring is all
Even, obtain reactant mixture L；
B) at 80 DEG C, oxygen flow is 200mL/min to reactant mixture L, reacts 10h, chromatograph monitoring raw material disappears；
C) filter, leach activated carbon, organic layer recycling design, obtain 5- bromo indole product 25.32g, yield 85.25%,
Content >=98%.
Claims (7)
1. a kind of green synthesis method of medicine intermediate 5- bromo indole destroys it is characterised in that first passing through low pressure liquid-phase hydrogenatin
Indole five-membered ring is conjugated, and nitrogen is protected, through green bromination technique, obtains high-purity bromination product, through deprotection, oxygen
The crucial medicine intermediate 5- bromo indole of fluidized dehydrogenation preparation；Detailed process is as follows：
1. indoline is obtained through low-temp low-pressure liquid-phase hydrogenatin by indole；2. indoline and acylating reagent are synthesized N- acetyl group
Indoline；3. the cleaned bromination of N- acetylindole quinoline obtains N- acetyl group -5--bromo indole quinoline；4. N- acetyl group -5- bromo indole
Quinoline deacylation in the presence of concentrated hydrochloric acid obtains 5--bromo indole quinoline；5. 5--bromo indole quinoline obtains in the middle of crucial medicine through oxidative dehydrogenation
Body 5- bromo indole.
2. a kind of green synthesis method of medicine intermediate 5- bromo indole according to claim 1 is it is characterised in that the party
The concrete operation step of method is as follows：
Step 1：The synthesis of indoline
A) indole, metallic catalyst, organic solvent are added in autoclave and stir, indole, metallic catalyst, You Jirong
The mass ratio 1 of agent:0.05～0.50:2～8 obtain reactant liquor A；
B), through nitrogen, after hydrogen is sufficiently displaced from, reactant liquor A is in H for autoclave2Pressure is 1～2.50Mpa, 70～150 DEG C of temperature
Reaction；
C) hydrogenated mixture that step b) obtains is filtered, filter out catalyst, obtain liquor B；
D) after liquor B reclaims organic solvent, put in vacuum distillation kettle, collect 65 DEG C/1.33 × 10-3The fraction of Mpa, obtains
Indoline product；
Step 2：N- acetylindole quinoline synthesizes
A) indoline, halogenated hydrocarbon solvent are put in reaction bulb, obtain reactant mixture C；
B), to Deca acylating reagent in mixture C, after completion of dropping, monitor and disappear to raw material.Indoline, acylating reagent, halo
The mol ratio of hydrocarbon solvent is 1:1～2:1～20,0～50 DEG C of reaction, obtains mixture D；
C) N- acetylindole quinoline product will after mixture D recycling design, be obtained；
Step 3：The synthesis of N- acetyl group -5--bromo indole quinoline
A) N- acetylindole quinoline, bromating agent, halogenated hydrocarbon solvent are put in reaction bulb, stir, N- acetylindole
Quinoline, bromating agent, the mol ratio of halogenated hydrocarbon solvent are 1:0.50～2:2～20, obtain reactant mixture E；
B) reactant mixture E reacts at 0～45 DEG C, obtains mixture F；
C) the saturated aqueous solution neutralization of mixture F sodium sulfite, until redness is wholly absent in reactant liquor, saturation sulfurous acid
The quality of hydrogen sodium and reactant liquor F are than for 1:1～10, point liquid, obtain organic faciess G and aqueous phase H；
D) organic faciess G are washed, and the water yield is 1～5 with the mass ratio of organic faciess:1；
E), after the recovered solvent of organic faciess G that step (d) obtains, obtain N- acetyl group -5--bromo indole quinoline product；
Step 4：The synthesis of 5--bromo indole quinoline
A) N- acetyl group -5--bromo indole quinoline, concentrated hydrochloric acid, alcohols solvent are put in reaction bulb, stir, N- acetyl group -
5--bromo indole quinoline, concentrated hydrochloric acid, the mol ratio of alcohols solvent are 1:0.50～5：0.50～5, obtain reactant mixture I；
B) reactant mixture I, at 30～100 DEG C, reacts 4～8h, and chromatograph monitoring raw material disappears；
C) it is neutralized to pH=5～11 with aqueous slkali, the mass ratio of the concentrated hydrochloric acid in alkali and reactant liquor I is 1～5:1, aqueous slkali
Mass percent is 5%～50%；
D) it is layered, obtain organic faciess J and aqueous phase K；
E) recycling design, obtains 5--bromo indole quinoline product；
Step 5:The synthesis of 5- bromo indole
A) 5--bromo indole quinoline, dehydrogenation, solvent are put in reaction bulb, stir, 5--bromo indole quinoline, catalysis dehydrogenation
Agent, the mass ratio of solvent are 1:0.50～5:1～10, obtain reactant mixture L；
B) at 40～150 DEG C, oxidizer flow rate is 100～400mL/min to reactant mixture L, reacts 7～40h, chromatograph monitoring is former
Material disappears；
C) filter, leach dehydrogenation, obtain organic layer M, recycling design, obtain 5- bromo indole product.
3. a kind of green synthesis method of medicine intermediate 5- bromo indole according to claim 2 is it is characterised in that step
Metallic catalyst described in 1 is palladium carbon, ruthenium charcoal, platinum charcoal, Raney's nickel and nickel/Al2O3One of；Organic solvent be toluene,
One of dimethylbenzene or its mixture.
4. a kind of green synthesis method of medicine intermediate 5- bromo indole according to claim 2 is it is characterised in that step
Acylating reagent described in 2 is one of acetic anhydride, chloroacetic chloride, propionyl chloride, and solvent is dichloromethane, chloroform, two chloroethenes
A kind of or its mixture in alkane, 1,2- dichloroethanes.
5. a kind of green synthesis method of medicine intermediate 5- bromo indole according to claim 2 is it is characterised in that step
Bromating agent described in 3 is DBDMH, NBS, hydrobromic acid/H2O2；Solvent is dichloromethane, chloroform, dichloroethanes or 1,
One of 2- dichloroethanes or its mixture.
6. a kind of green synthesis method of medicine intermediate 5- bromo indole according to claim 2 is it is characterised in that step
Acid described in 4 is hydrochloric acid, and solvent is one of methanol, ethanol or its mixture.
7. medicine intermediate 5- bromo indole according to claim 2 a kind of green synthesis method it is characterised in that：Step
Oxidant described in 5 is one of air, oxygen；Catalyst is a kind of in activated carbon, Carbon foam and NACF；Molten
Agent is one of toluene, dimethylbenzene or its mixture.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106966950A (en) * | 2017-04-17 | 2017-07-21 | 兰州大学 | A kind of preparation method of the bromo indole of pharmaceutical intermediate 5 |
| CN107501166A (en) * | 2017-08-30 | 2017-12-22 | 南京理工大学 | The synthetic method of indoles and norborneol alkanes and its derivative |
| CN107987076A (en) * | 2017-12-28 | 2018-05-04 | 中钢集团鞍山热能研究院有限公司 | A kind of synthetic method of 5- bromo-7-azaindoles |
| CN111454192A (en) * | 2019-01-22 | 2020-07-28 | 上海隆盛化工有限公司 | Efficient synthesis process of medical intermediate 5-bromoindole |
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| WO2008111474A1 (en) * | 2007-03-09 | 2008-09-18 | Japan Envirochemicals, Ltd. | Process for production of indole compound |
| CN102558017A (en) * | 2011-12-27 | 2012-07-11 | 郑州凯美克化学有限公司 | Method for preparing 5-bromoindole |
| CN103183629A (en) * | 2013-03-15 | 2013-07-03 | 张家港威胜生物医药有限公司 | Process of effectively synthesizing important pharmaceutical and chemical intermediate 5-bromoindole |
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| WO2008111474A1 (en) * | 2007-03-09 | 2008-09-18 | Japan Envirochemicals, Ltd. | Process for production of indole compound |
| CN102558017A (en) * | 2011-12-27 | 2012-07-11 | 郑州凯美克化学有限公司 | Method for preparing 5-bromoindole |
| CN103183629A (en) * | 2013-03-15 | 2013-07-03 | 张家港威胜生物医药有限公司 | Process of effectively synthesizing important pharmaceutical and chemical intermediate 5-bromoindole |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106966950A (en) * | 2017-04-17 | 2017-07-21 | 兰州大学 | A kind of preparation method of the bromo indole of pharmaceutical intermediate 5 |
| CN107501166A (en) * | 2017-08-30 | 2017-12-22 | 南京理工大学 | The synthetic method of indoles and norborneol alkanes and its derivative |
| CN107987076A (en) * | 2017-12-28 | 2018-05-04 | 中钢集团鞍山热能研究院有限公司 | A kind of synthetic method of 5- bromo-7-azaindoles |
| CN111454192A (en) * | 2019-01-22 | 2020-07-28 | 上海隆盛化工有限公司 | Efficient synthesis process of medical intermediate 5-bromoindole |
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