CN110386892A - A kind of preparation method of the fluoro- 5- hydroxy-2-methyl -1H- indoles of 4- - Google Patents
A kind of preparation method of the fluoro- 5- hydroxy-2-methyl -1H- indoles of 4- Download PDFInfo
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- CN110386892A CN110386892A CN201810336663.9A CN201810336663A CN110386892A CN 110386892 A CN110386892 A CN 110386892A CN 201810336663 A CN201810336663 A CN 201810336663A CN 110386892 A CN110386892 A CN 110386892A
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- 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
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Abstract
The present invention provides a kind of preparation method of fluoro- 5- hydroxy-2-methyl -1H- indoles of 4-, it is raw material using the halogenated -6- nitrotoleune of the fluoro- 3- of 2-, it is substituted with alcohol and reacts the preparation fluoro- 3-GO substituent group -6- nitrotoleune of 2-, then 1- (the fluoro- 3-GO substituent group -6- nitrobenzophenone of 2-) -2- alkoxy propylene is obtained through condensation reaction with three ester of ortho-acetic acid, then obtains the fluoro- 5- hydroxy-2-methyl -1H- indoles of 4- through reduction-cyclization.The method of the present invention safe green, easy to operate, at low cost, selectivity is high, final product yield and purity is high.
Description
Technical field
The present invention relates to a kind of preparation methods of the fluoro- 5- hydroxy-2-methyl -1H- indoles of 4-, belong to medical chemistry technology neck
Domain.
Background technique
Hydrochloric acid pacifies sieve and replaces Buddhist nun (Anlotinib Hydrochloride), is a kind of novel multiple target point of China's independent research
Tyrosine kinase inhibitor can effectively inhibit the kinases such as VEGFR, PDGFR, FGFR, c-Kit, have Antineoplastic angiogenesis and
Inhibit the effect of tumour growth.Hydrochloric acid peace sieve obtained the Orphan drug qualification that U.S. FDA authorizes treatment oophoroma in 2015 for Buddhist nun
Assert, currently used for three line of advanced NSCLC treatment III phase research (ALTER-0303) simultaneously successfully reach treatment terminal, and into
Enter Chinese CFDA expedited review channel, being expected to, which becomes Chinese three line of advanced NSCLC, treats standard, and in treatment oophoroma, uterus
Endometrial carcinomas and other kinds cancers for example soft tissue sarcoma, gastric cancer, colorectal cancer, medullary carcinoma of thyroid gland, differentiated thyroid carcinoma with
And good treatment prospect is showed in esophageal squamous cell carcinoma.
Si Dinibu (Cediranib), also known as AZD2171 are a kind of general blood vessel endotheliums of Astrazeneca AB's exploitation
The potent inhibitor of growth factor (pan-VEGF) receptor tyrosine kinase, Si Dinibu and olaparib (Olaparib) compounding
Can be used for treating recurrent ovarian carcinoma, and two medicines have synergistic effect and tolerance well, curative effect and Ni Lapani are suitable, but
It is, the advantages such as treatment cost low convenient with medication.
And the fluoro- 5- hydroxy-2-methyl -1H- indoles (I) of 4- is the key that prepare hydrochloric acid peace sieve to replace Buddhist nun and Si Dinibu intermediate
Body.
It is as follows for the structural formula of Buddhist nun, Si Dinibu and the fluoro- 5- hydroxy-2-methyl -1H- indoles (I) of 4- that hydrochloric acid pacifies sieve；
Patent document CN101809012A describes the synthetic route that three kinds of hydrochloric acid peace sieve replace Buddhist nun, patent document
CN103275069A and CN102603718A proposes the preparation method of Si Dinibu, wherein using the fluoro- 5- hydroxyl -2- first of 4-
Base -1H- indoles as key intermediate, but about the preparation method of the fluoro- 5- hydroxy-2-methyl -1H- indoles of 4- report compared with
It is few.Currently, preparation method mainly report it is as follows:
Patent document US2011257395 and WO2008053221 describe the fluoro- 5- hydroxy-2-methyl -1H- indoles of 4-
Preparation method is that raw material and tert-butyl acetoacetate prepare 2- (2,3- in the presence of highly basic sodium alkoxide with 2,3,4- trifluoronitrobenzenes
Two fluoro- 6- nitrobenzophenones) -3- oxo n-butyric acie the tert-butyl ester, then with Triton B (N, N, N- trimethylbenzene first ammonium hydroxide
Object) substituted in reaction nitro contraposition fluorine atom preparation 2- (the fluoro- 3- hydroxyl -6- nitrobenzophenone of 2-) -3- oxo n-butyric acie tert-butyl ester, then
- 2 ketone of 1- (the fluoro- 3- hydroxyl -6- nitrobenzophenone of 2-) propyl is obtained through aqueous sulfuric acid hydrolysis decarboxylation, through sodium hydrosulfite reductive cyclization system
The standby fluoro- 5- hydroxy-2-methyl -1H- indoles of 4-, report total recovery are 50.3%, and reaction process is described as following synthetic route 1.
Chinese patent literature CN102603718A is raw material and ethyl acetoacetate in highly basic with 2,3,4- trifluoronitrobenzenes
2- (2,3- bis- fluoro- 6- nitrobenzophenone) -3- oxo ethyl butyrate is prepared in the presence of sodium ethoxide, then in concentrated hydrochloric acid and glacial acetic acid
Hydrolysis decarboxylation obtains -2 ketone of 1- (2,3- bis- fluoro- 6- nitrobenzophenone) propyl under the nitration mixture of composition, is replacing nitro contraposition with benzylalcohol
Fluorine atom prepares 1- (the fluoro- 6- nitrobenzophenone of 3- benzyloxy -2-) propyl -2- ketone, obtains 5- benzyloxy-through sodium hydrosulfite reductive cyclization
The fluoro- 2- Methyl-1H-indole of 4-, then the fluoro- 5- hydroxy-2-methyl -1H- indoles of 4- is obtained through palladium charcoal catalytic hydrogenolysis, report total recovery
It is 44.3%, reaction process is described as following synthetic route 2.
Both the above method preparation route step is more, and 2,3,4- trifluoronitrobenzenes and acetoacetic ester carbanion take
When generation reaction, quite, selectivity is low, and purifying products require high for the Fluorine atom activity of nitro ortho position and contraposition.In addition used
The prices such as 2,3,4- trifluoronitrobenzenes, highly basic, Triton B are high, and hydrolysis decarboxylation acid consumption is big, and wastewater flow rate is big, and the feature of environmental protection is poor, no
It is reduced conducive to green industrialized production and cost.
Summary of the invention
In view of the deficiencies of the prior art, the present invention provides a kind of safe green, the fluoro- 5- hydroxyl of 4- easy to operate, at low cost
The preparation method of base -2- Methyl-1H-indole.Method choice of the invention is high, final product yield and purity is high.
Term explanation:
II compound of formula: the halogenated -6- nitrotoleune of the fluoro- 3- of 2-；
III compound of formula: the fluoro- 3-GO substituent group -6- nitrotoleune of 2-, wherein GO is benzyloxy, to methylbenzyloxy or right
Methoxybenzyl oxygroup；
Formula IV compound: 1- (the fluoro- 3-GO substituent group -6- nitrobenzophenone of 2-) -2- alkoxy propylene, wherein GO is benzyloxy
Base, to methylbenzyloxy or to methoxybenzyl oxygroup；
Type I compound: the fluoro- 5- hydroxy-2-methyl -1H- indoles of 4-.
Compound number and formula numbers in this specification is completely the same, reference relationship having the same, with chemical combination
Object structural formula is foundation.
A kind of preparation method of the fluoro- 5- hydroxy-2-methyl -1H- indoles of 4-, comprising steps of
(1) in solvent A, in the presence of acid binding agent, II compound of formula is substituted with the alcohol that general formula is GOH reacts preparation
III compound of formula；
Wherein, in II structural formula of compound of formula, X Cl, Br or I；General formula is the pure and mild formula III structural formula of compound of GOH
In, G has the same meaning, and is benzyl, to methylbenzyl or to methoxy-benzyl；
(2) in solvent B or in the presence of solvent-free, under the action of catalyst 1, III compound of formula and three ester of ortho-acetic acid
Formula IV compound is obtained through condensation reaction；
Wherein, in formula IV structural formula of compound, R is methyl or ethyl, G in the meaning and formula III structural formula of compound of G
Meaning is identical；
(3) in solvent C, under the action of catalyst 2, formula IV compound obtains the fluoro- 5- hydroxyl of 4- through reduction-cyclization
Base -2- Methyl-1H-indole (I).
, according to the invention it is preferred to, solvent A described in step (1) is n,N-Dimethylformamide, N, N- dimethylacetamide
One or both of amine, tetrahydrofuran, 2- methyltetrahydrofuran, methyl ring amyl ether, 1,2- dimethoxy-ethane or chlorobenzene with
On combination；The mass ratio of II compound of the solvent A and formula is (5-25): 1；Preferably, II compound of the solvent A and formula
Mass ratio be (7-15): 1.
, according to the invention it is preferred to, acid binding agent described in step (1) is in potassium carbonate, sodium carbonate, cesium carbonate or calcium carbonate
A combination of one or more.
, according to the invention it is preferred to, acid binding agent described in step (1), II compound of pure and mild formula molar ratio be (1.0-
2.0):(1.0-2.0):1。
, according to the invention it is preferred to, substitution reaction temperature described in step (1) is 60-150 DEG C；Preferably, the substitution
Reaction temperature is 80-110 DEG C.The substitution reaction time is 2-10 hours；Preferably, the substitution reaction time is 3-6 hours.
, according to the invention it is preferred to, solvent B described in step (2) be hexamethylene, n-hexane, petroleum ether, tetrahydrofuran,
2- methyltetrahydrofuran, methyl ring amyl ether, one in three ester of 1,2- dimethoxy-ethane, N,N-dimethylformamide or ortho-acetic acid
Kind or two or more combinations；The mass ratio of III compound of the solvent B and formula is (3-15): 1；Preferably, the solvent B and
The mass ratio of III compound of formula is (5-10): 1.
, according to the invention it is preferred to, catalyst 1 described in step (2) be Lewis acid, preferably zinc chloride, iron chloride,
Aluminium chloride or stannous chloride；The quality of the catalyst 1 is the 0.5%~10% of III compound quality of formula；Preferably, described to urge
The quality of agent 1 is the 1%~5% of III compound quality of formula.
, according to the invention it is preferred to, three ester of ortho-acetic acid described in step (2) is three second of trimethyl orthoacetate or ortho-acetic acid
Ester；The molar ratio of three ester of ortho-acetic acid and III compound of formula is (1.0-6.0): 1.
, according to the invention it is preferred to, setting-up point described in step (2) is 20-100 DEG C；Preferably, the condensation
Reaction temperature is 60-80 DEG C.Condensation reaction time is 2-10 hours；Preferably, condensation reaction time is 3-6 hours.
, according to the invention it is preferred to, solvent C described in step (3) is methanol, ethyl alcohol, acetonitrile, ethyl acetate, tetrahydro furan
It mutters, the combination of one or more of 2- methyltetrahydrofuran, methyl ring amyl ether or 1,2- dimethoxy-ethane；It is described molten
The mass ratio of agent C and formula IV compound is (5-25): 1；Preferably, the mass ratio of the solvent C and formula IV compound is (8-
15):1。
, according to the invention it is preferred to, catalyst 2 described in step (3) is palladium charcoal or Raney Ni；Preferably, the matter of palladium charcoal
Amount is the 0.5%~10% of formula IV compound quality；It is further preferred that the quality of palladium charcoal is the 1% of formula IV compound quality
~5%, the mass content of palladium is 5% in palladium carbon；Preferably, the quality of Raney Ni is the 5%~25% of formula IV compound quality；
It is further preferred that the quality of Raney Ni is the 10%~15% of formula IV compound quality, the mass content of nickel is in Raney Ni
50%.
, according to the invention it is preferred to, reduction described in step (3)-cyclization temperature is 20~100 DEG C, reduction-cyclisation
Reducing agent used in reduction reaction is hydrogen, Hydrogen Vapor Pressure 0.1-0.5MPa in reaction；Preferably, the reduction-cyclization
Temperature is 30~60 DEG C, Hydrogen Vapor Pressure 0.2-0.4MPa.Reduction-cyclization time is 3~10 hours；Preferably, reduction-
The cyclization time is 4-8 hours.
Sieve can be pacified by prior art preparation hydrochloric acid using the fluoro- 5- hydroxy-2-methyl -1H- indoles of 4- obtained by the present invention and replace Buddhist nun
And Si Dinibu.
The present invention is described as following synthetic route 3:
It technical characterstic of the invention and has the beneficial effect that:
1, the present invention provides a kind of preparation methods of the fluoro- 5- hydroxy-2-methyl -1H- indoles of 4-, utilize the fluoro- 3- halogen of 2-
Generation -6- nitrotoleune be raw material, be substituted with alcohol react prepare the fluoro- 3-GO substituent group -6- nitrotoleune of 2-, then with ortho-acetic acid
Three esters obtain 1- (the fluoro- 3-GO substituent group -6- nitrobenzophenone of 2-) -2- alkoxy propylene through condensation reaction, then anti-through reduction-cyclisation
It should obtain the fluoro- 5- hydroxy-2-methyl -1H- indoles of 4-.
2, the method for the present invention process flow is brief, only 3 steps is needed to can be prepared by final product, reaction condition is mild, is easy to grasp
Make；Hydrolysis decarboxylation reaction it is not related to, wastewater flow rate is few, green safe environmental protection；Raw material is cheap and easy to get, and product cost is low；Products obtained therefrom
Purity and high income, total recovery are suitable for green industrialized production up to 86%.
3, the present invention has fully demonstrated quality derived from the theory of design, and involved unit operation ensure that chemical reaction function
The reaction specificity and suitable active of group, general formula are that the hydroxyl of the alcohol of GOH and the single halogen activated by contraposition nitro occur
Substitution reaction, selectivity are 100%, avoid more active positions in background technique；Condensation reaction with three ester of ortho-acetic acid is only
The ortho methyl group activated by nitro can be betided, and in subsequent reduction-cyclization, nitro is easy to be reduced to ammonia
Base, while alcohol cyclisation is removed, the fluoro- 5- hydroxy-2-methyl -1H- indoles of 4- is obtained, reaction selectivity is high.
4, for Buddhist nun and Xi Buddhist nun hydrochloric acid peace sieve can be prepared using the fluoro- 5- hydroxy-2-methyl -1H- indoles of 4- obtained by the present invention
Cloth is of great significance for its industrialized production.
Specific embodiment
The present invention is described in detail with reference to embodiments, but the present invention is not only limited to this.
Embodiment is raw materials used and reagent is commercial product." % " in embodiment is mass percent, is illustrated
Except.
The preparation of the fluoro- 3- benzyloxy -6- nitrotoleune (III 1) of embodiment 1:2-
To be connected to stirring, thermometer, reflux condensing tube 500 milliliters of four-hole boiling flasks in, 200 grams of N, N- dimethyl methyl is added
Amide, 23.4 grams of bromo- 6- nitrotoleunes (II 1) of (0.1 mole) fluoro- 3- of 2-, 16.2 grams of (0.15 mole) benzylalcohols, 20.7 grams
(0.15 mole) potassium carbonate, 105 to 110 DEG C are stirred to react 3 hours.20 to 25 DEG C are cooled to, sylvite is filtered to remove, it is molten with 30 grams
Filter cake, merging filtrate are washed in agent, then 0.5 gram of active carbon, 150 gram 80% is added in vacuum distillation recovered solvent into residue
Ethyl alcohol, 80 DEG C of reaction stirrings are decolourized 1 hour, are filtered while hot, and cooling recrystallization filters, dry, obtain the fluoro- 3- benzyl of 24.3 grams of 2-
Oxygroup -6- nitrotoleune (III 1), yield 93.1%, liquid phase purity 99.3%.
The preparation of the fluoro- 3- benzyloxy -6- nitrotoleune (III 1) of embodiment 2:2-
To be connected to stirring, thermometer, reflux condensing tube 500 milliliters of four-hole boiling flasks in, 200 grams of N, N- dimethyl methyl is added
Amide, 28.2 grams of iodo- 6- nitrotoleunes (II 2) of (0.1 mole) fluoro- 3- of 2-, 13.0 grams of (0.12 mole) benzylalcohols, 20.7 grams
(0.15 mole) potassium carbonate, 90 to 95 DEG C are stirred to react 5 hours.20 to 25 DEG C are cooled to, sylvite is filtered to remove, with 30 grams of solvents
Filter cake, merging filtrate are washed, then 0.5 gram of active carbon, 150 gram of 80% second is added in vacuum distillation recovered solvent into residue
Alcohol, 80 DEG C of reaction stirrings are decolourized 1 hour, are filtered while hot, and cooling recrystallization filters, dry, obtain the fluoro- 3- benzyloxy of 24.7 grams of 2-
Base -6- nitrotoleune (III 1), yield 94.6%, liquid phase purity 99.4%.
The preparation of the fluoro- 3- of embodiment 3:2- (4- methoxyl group) benzyloxy -6- nitrotoleune (III 2)
To be connected to stirring, thermometer, reflux condensing tube 500 milliliters of four-hole boiling flasks in, 200 grams of N, N- dimethyl methyl is added
Amide, 23.5 grams of bromo- 6- nitrotoleunes (II 1) of (0.1 mole) fluoro- 3- of 2-, 16.7 grams of (0.12 mole) 4- methoxyl group benzylalcohols,
20.7 grams of (0.15 mole) potassium carbonate, 100 to 105 DEG C are stirred to react 4 hours.20 to 25 DEG C are cooled to, sylvite is filtered to remove, is used
30 grams of solvents wash filter cake, merging filtrate, then 0.5 gram of active carbon, 150 are added in vacuum distillation recovered solvent into residue
Gram 80% ethyl alcohol, 80 DEG C reactions stirring decoloration 1 hour, filter while hot, cooling recrystallization filters, dry, obtains 25.7 grams of 2-
Fluoro- 3- (4- methoxyl group) benzyloxy -6- nitrotoleune (III 2), yield 88.2%, liquid phase purity 99.2%.
The preparation of embodiment 4:1- (the fluoro- 3- benzyloxy -6- nitrobenzophenone of 2-) -2- methoxyl group propylene (IV1)
To be connected to stirring, thermometer, reflux condensing tube 250 milliliters of four-hole boiling flasks in, 100 grams of tetrahydrofurans are added,
13.1 grams (0.05 mole) the fluoro- 3- benzyloxy -6- nitrotoleunes (III 1) of the 2- being made by embodiment 1,18.0 grams (0.15 mole)
Trimethyl orthoacetate, 0.4 gram of zinc chloride, 65 to 70 DEG C are stirred to react 5 hours.It is distilled to recover solvent and excessive ortho-acetic acid front three
Ester obtains 16.1 grams of faint yellow dope 1- (the fluoro- 3- benzyloxy -6- nitrobenzophenone of 2-) -2- methoxyl group propylene (IV1), directly
For embodiment 7.
The system of embodiment 5:1- (the fluoro- 3- of 2- (4- methoxyl group) benzyloxy -6- nitrobenzophenone) -2- methoxyl group propylene (IV2)
It is standby
To be connected to stirring, thermometer, reflux condensing tube 250 milliliters of four-hole boiling flasks in, 100 grams of tetrahydrofurans are added,
14.6 grams of (0.05 mole) 2- as made from embodiment 3 fluoro- 3- (4- methoxyl group) benzyloxy -6- nitrotoleunes (III 2), 18.0 grams
(0.15 mole) trimethyl orthoacetate, 0.5 gram of stannous chloride, 65 to 70 DEG C are stirred to react 5 hours.It is distilled to recover solvent and excess
Trimethyl orthoacetate obtains 18.2 grams of faint yellow dope 1- (the fluoro- 3- of 2- (4- methoxyl group) benzyloxy -6- nitrobenzophenone) -2-
Methoxyl group propylene (IV2), is directly used in embodiment 8.
The preparation of embodiment 6:1- (the fluoro- 3- benzyloxy -6- nitrobenzophenone of 2-) -2- ethoxy propylene (IV3)
To be connected to stirring, thermometer, reflux condensing tube 250 milliliters of four-hole boiling flasks in, be added 13.1 grams (0.05 mole)
The fluoro- 3- benzyloxy -6- nitrotoleune (III 1) of the 2- as made from embodiment 2,50.0 grams of (0.3mol) triethly orthoacetates, 0.6 gram
Zinc chloride, 75 to 80 DEG C are stirred to react 5 hours, and excessive triethly orthoacetate is recycled in vacuum distillation, obtain 16.4 grams it is faint yellow viscous
Thick object 1- (the fluoro- 3- benzyloxy -6- nitrobenzophenone of 2-) -2- ethoxy propylene (IV3), is directly used in embodiment 9.
The preparation of the fluoro- 5- hydroxy-2-methyl -1H- indoles (I) of embodiment 7:4-
150 grams of methanol, 4 16.1 grams of faint yellow dope 1- of gained of embodiment are added into 500 milliliters of stainless steel pressure kettles
(the fluoro- 3- benzyloxy -6- nitrobenzophenone of 2-) -2- methoxyl group propylene (IV1), 0.5 gram of 5wt% palladium-carbon catalyst, nitrogen displacement three
After secondary, it is passed through hydrogen, holding system pressure is 0.2-0.3MPa, and 55-60 DEG C is reacted 4 hours.Nitrogen is replaced three times, is filtered to remove
Palladium carbon, methanol wash filter cake twice, every time 30 grams of methanol, merging filtrate.Distillation filtrate recycling design, dry 7.53 grams of 4-
Fluoro- 5- hydroxy-2-methyl -1H- indoles (I), with III 1 compound calculated yields for 91.3%, liquid phase purity 99.5%.
The nuclear magnetic data of products therefrom is as follows:
1HNMR(400MHz,DMSO-d6):δppm
10.82(br,s,1H),8.72(s,1H),6.86(d,1H),6.64(t,1H),6.02-6.04(m,1H),2.28
(s,3H).
The preparation of the fluoro- 5- hydroxy-2-methyl -1H- indoles (I) of embodiment 8:4-
150 grams of acetonitriles, 5 18.2 grams of faint yellow dope 1- of gained of embodiment are added into 500 milliliters of stainless steel pressure kettles
(the fluoro- 3- of 2- (4- methoxyl group) benzyloxy -6- nitrobenzophenone) -2- methoxyl group propylene (IV2), 2.3 grams of 50wt% Raney Ni catalysis
Agent after nitrogen displacement three times, is passed through hydrogen, and holding system pressure is 0.3-0.4MPa, and 50-55 DEG C is reacted 5 hours.Nitrogen displacement
Three times, Filtration of catalyst, acetonitrile wash filter cake twice, and 30 grams every time, merging filtrate.Distillation filtrate recycling design, it is dry
The fluoro- 5- hydroxy-2-methyl -1H- indoles (I) of 7.40 grams of 4- is obtained, with III 2 compound calculated yields for 89.7%, liquid phase purity
99.4%.
The preparation of the fluoro- 5- hydroxy-2-methyl -1H- indoles (I) of embodiment 9:4-
150 grams of methanol, 6 16.4 grams of faint yellow dope 1- of gained of embodiment are added into 500 milliliters of stainless steel pressure kettles
(the fluoro- 3- benzyloxy -6- nitrobenzophenone of 2-) -2- ethoxy propylene (IV3), 0.5 gram of 5wt% palladium-carbon catalyst, nitrogen displacement three
After secondary, it is passed through hydrogen, holding system pressure is 0.2-0.3MPa, and 45-50 DEG C is reacted 6 hours.Nitrogen is replaced three times, is filtered to remove
Palladium carbon, methanol wash filter cake twice, every time 30 grams of methanol, merging filtrate.Distillation filtrate recycling design, dry 7.51 grams of 4-
Fluoro- 5- hydroxy-2-methyl -1H- indoles (I), with III 1 compound calculated yields for 91.0%, liquid phase purity 99.7%.
Comparative example: the preparation of the fluoro- 3- benzyloxy -6- nitrotoleune (III 1) of 2-
To be connected to stirring, thermometer, reflux condensing tube 500 milliliters of four-hole boiling flasks in, 200 grams of N, N- dimethyl methyl is added
Amide, 23.4 grams of bromo- 6- nitrotoleunes (II 1) of (0.1 mole) fluoro- 3- of 2-, 16.2 grams of (0.15 mole) benzylalcohols, 6.9 gram (0.05
Mole) potassium carbonate, 105 to 110 DEG C are stirred to react 4 hours.20 to 25 DEG C are cooled to, sylvite is filtered to remove, is washed with 30 grams of solvents
Filter cake, merging filtrate are washed, then 0.5 gram of active carbon, 150 gram of 80% ethyl alcohol is added in vacuum distillation recovered solvent into residue,
80 DEG C of reaction stirrings are decolourized 1 hour, are filtered while hot, and cooling recrystallization filters, dry, obtain the fluoro- 3- benzyloxy-of 19.4 grams of 2-
6- nitrotoleune (III 1), yield 74.3%, liquid phase purity 98.2%.
Comparative example shows that the type of acid binding agent used and dosage are suitable, when as in acid binding agent with halogen acids, to avoid
The generation of water, otherwise, the water of generation cause II 1 compound hydrolysis of formula generate the fluoro- 3- hydroxyl -6- nitrotoleune of 2-, and cause into
One step dimerization, and reduce target product yield and purity.
Claims (10)
1. a kind of preparation method of the fluoro- 5- hydroxy-2-methyl -1H- indoles of 4-, comprising steps of
(1) in solvent A, in the presence of acid binding agent, II compound of formula is substituted with the alcohol that general formula is GOH reacts preparation formula III
Compound；
Wherein, in II structural formula of compound of formula, X Cl, Br or I；General formula is G in the pure and mild formula III structural formula of compound of GOH
It has the same meaning, is benzyl, to methylbenzyl or to methoxy-benzyl；
(2) in solvent B or in the presence of solvent-free, under the action of catalyst 1, III compound of formula is with three ester of ortho-acetic acid through contracting
It closes reaction and obtains formula IV compound；
Wherein, in formula IV structural formula of compound, R is methyl or ethyl, the meaning of G in the meaning and formula III structural formula of compound of G
It is identical；
(3) in solvent C, under the action of catalyst 2, formula IV compound obtains the fluoro- 5- hydroxyl-of 4- through reduction-cyclization
2- Methyl-1H-indole (I).
2. the preparation method of the fluoro- 5- hydroxy-2-methyl -1H- indoles of 4- according to claim 1, which is characterized in that step
(1) solvent A described in is N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, tetrahydrofuran, 2- methyltetrahydrofuran, first
The combination of one or more of basic ring amyl ether, 1,2- dimethoxy-ethane or chlorobenzene；II compound of the solvent A and formula
Mass ratio be (5-25): 1；Preferably, the mass ratio of II compound of the solvent A and formula is (7-15): 1.
3. the preparation method of the fluoro- 5- hydroxy-2-methyl -1H- indoles of 4- according to claim 1, which is characterized in that step
(1) acid binding agent described in is the combination of one or more of potassium carbonate, sodium carbonate, cesium carbonate or calcium carbonate.
4. the preparation method of the fluoro- 5- hydroxy-2-methyl -1H- indoles of 4- according to claim 1, which is characterized in that step
(1) acid binding agent described in, II compound of pure and mild formula molar ratio be (1.0-2.0): (1.0-2.0): 1.
5. the preparation method of the fluoro- 5- hydroxy-2-methyl -1H- indoles of 4- according to claim 1, which is characterized in that step
(1) substitution reaction temperature described in is 60-150 DEG C；Preferably, the substitution reaction temperature is 80-110 DEG C.
6. the preparation method of the fluoro- 5- hydroxy-2-methyl -1H- indoles of 4- according to claim 1, which is characterized in that step
(2) in, including one or more in the following conditions:
A, the solvent B is hexamethylene, n-hexane, petroleum ether, tetrahydrofuran, 2- methyltetrahydrofuran, methyl ring amyl ether, 1,2-
The combination of one or more of three ester of dimethoxy-ethane, N,N-dimethylformamide or ortho-acetic acid；The solvent B and
The mass ratio of III compound of formula is (3-15): 1；Preferably, the mass ratio of III compound of the solvent B and formula is (5-10): 1；
B, the catalyst 1 is Lewis acid, preferably zinc chloride, iron chloride, aluminium chloride or stannous chloride；The catalyst 1
Quality is the 0.5%~10% of III compound quality of formula；Preferably, the quality of the catalyst 1 is III compound quality of formula
1%~5%；
C, three ester of ortho-acetic acid is trimethyl orthoacetate or triethly orthoacetate；Three ester of ortho-acetic acid and III compound of formula
Molar ratio is (1.0-6.0): 1.
7. the preparation method of the fluoro- 5- hydroxy-2-methyl -1H- indoles of 4- according to claim 1, which is characterized in that step
(2) setting-up point described in is 20-100 DEG C；Preferably, the setting-up point is 60-80 DEG C.
8. the preparation method of the fluoro- 5- hydroxy-2-methyl -1H- indoles of 4- according to claim 1, which is characterized in that step
(3) solvent C described in be methanol, ethyl alcohol, acetonitrile, ethyl acetate, tetrahydrofuran, 2- methyltetrahydrofuran, methyl ring amyl ether or
The combination of one or more of 1,2- dimethoxy-ethane；The mass ratio of the solvent C and formula IV compound is (5-
25):1；Preferably, the mass ratio of the solvent C and formula IV compound is (8-15): 1.
9. the preparation method of the fluoro- 5- hydroxy-2-methyl -1H- indoles of 4- according to claim 1, which is characterized in that step
(3) catalyst 2 described in is palladium charcoal or Raney Ni；Preferably, the quality of palladium charcoal be formula IV compound quality 0.5%~
10%；It is further preferred that the quality of palladium charcoal is the 1%~5% of formula IV compound quality, the mass content of palladium is in palladium carbon
5%；Preferably, the quality of Raney Ni is the 5%~25% of formula IV compound quality；It is further preferred that the quality of Raney Ni
It is the 10%~15% of formula IV compound quality, the mass content of nickel is 50% in Raney Ni.
10. the preparation method of the fluoro- 5- hydroxy-2-methyl -1H- indoles of 4- according to claim 1, which is characterized in that step
Suddenly reduction described in (3)-cyclization temperature is 20~100 DEG C, and reducing agent used in reduction reaction is hydrogen in reduction-cyclization
Gas, Hydrogen Vapor Pressure 0.1-0.5MPa；Preferably, the reduction-cyclization temperature is 30~60 DEG C, Hydrogen Vapor Pressure 0.2-
0.4MPa。
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Citations (3)
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|---|---|---|---|---|
| WO2003082271A2 (en) * | 2002-04-03 | 2003-10-09 | Astrazeneca Ab | Indole derivatives having anti-angiogenetic activity |
| CN102307870A (en) * | 2008-12-09 | 2012-01-04 | 诺瓦提斯公司 | Pyridyloxyindoles inhibitors of VEGF-R2 and their use for treating diseases |
| CN103588725A (en) * | 2013-10-29 | 2014-02-19 | 北京科技大学 | Preparation method for bis(rhodanine)merocyanine sensitizing dye with a benzothiazole skeloton |
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2018
- 2018-04-16 CN CN201810336663.9A patent/CN110386892B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003082271A2 (en) * | 2002-04-03 | 2003-10-09 | Astrazeneca Ab | Indole derivatives having anti-angiogenetic activity |
| CN102307870A (en) * | 2008-12-09 | 2012-01-04 | 诺瓦提斯公司 | Pyridyloxyindoles inhibitors of VEGF-R2 and their use for treating diseases |
| CN103588725A (en) * | 2013-10-29 | 2014-02-19 | 北京科技大学 | Preparation method for bis(rhodanine)merocyanine sensitizing dye with a benzothiazole skeloton |
Non-Patent Citations (1)
| Title |
|---|
| TAKAO SAKAMOTO ET AL.: "Condensed heteroaromatic ring systems.VI.Synthesis of indoles and pyrrolopyridines from o-nitroarylacetylenes", 《CHEMICAL & PHARMACEUTICAL BULLETIN》 * |
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