CN105732464A - Massive production method of indole compound - Google Patents
Massive production method of indole compound Download PDFInfo
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- CN105732464A CN105732464A CN201511026608.2A CN201511026608A CN105732464A CN 105732464 A CN105732464 A CN 105732464A CN 201511026608 A CN201511026608 A CN 201511026608A CN 105732464 A CN105732464 A CN 105732464A
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- indole
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- trimethoxybenzoy
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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
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/09—Geometrical isomers
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention relates to a synthesis method of an indole compound. The synthesis method comprises the following steps: in the presence of a first acylation reaction catalyst, carrying out acylation reactions among a primary indole compound, a chloro-acyl compound, and a second acylation reaction catalyst in an organic solvent; and extracting the indole compound; wherein the first acylation reaction catalyst is composed of a Grignard reagent and Lewis acids, the second acylation reaction catalyst is Lewis acids; the first acylation reaction catalyst can be added or not depending on the situations, and the temperature of acylation reactions is not higher than 25 DEG C.
Description
Technical field
The present invention relates to organic synthesis field, particularly a kind of method of large-scale production benzazolyl compounds.
Background technology
The correlational study of this area has been found that benzazolyl compounds has active anticancer.United States Patent (USP) 6933316B2 discloses benzazolyl compounds can become microtubule inhibitors by the mode of microtubule polymerization/go polymerization, thus the anticancer compound active as having resisting mitosis.Benzazolyl compounds has the possibility processing various malignant tumor, especially for having drug-fast patient.
Can synthesis of indole compound by the acylation reaction of indole.But, existing benzazolyl compounds synthetic method is all only limitted to the scope of laboratory applications, it is impossible to be applied to the large-scale production of benzazolyl compounds.In view of the presence of many considerations of the aspects such as productivity, cost, control and impurity, to the large-scale production of industry, has very big Unpredictability from the success of laboratory applications.
Summary of the invention
For above technical problem, present applicant proposes the synthetic method of benzazolyl compounds shown in a kind of Formulas I,
Including:
Starting indole shown in (i) Formula II and the first acylation reaction catalyst effect；
(ii) add chlorine acyl compounds shown in formula III, carry out acylation reaction with starting indole in organic solvent；
(iii) the second acylation reaction catalyst is added；
(iv) benzazolyl compounds is extracted.
One or more methods as above, the first acylation reaction catalyst is Grignard reagent and lewis acid.
One or more methods as above, the second acylation reaction catalyst is lewis acid.
One or more methods as above, L1For chemical bond, C (O), O, S, NR, SO2Or CH2。
One or more methods as above, L2For chemical bond, C (O), O, S, NR, SO2Or CH2。
One or more methods as above, RlFor alkyl, ring base, heterocyclic radical, aryl or heteroaryl.
One or more methods as above, R2For H, alkyl, ring base, heterocyclic radical, aryl, heteroaryl, halogen, nitro, nitroso-group, cyano group, repeatedly nitrilo, different sulfur nitro, OR, OC (O) R, OC (O) OR, OC (O) NRR', SO2R、SO3R、SO2NRR'、SR、NRR'、NRSO2NR'R"、NRSO2R'、NRSO3R', NRC (O) R', NRC (O) NR'R ", NRC (O) OR', NRC (N) NR'R ", C (O) OR or C (O) NRR'.
One or more methods as above, each Ra、Rb、RcWith RdRespectively R, halogen, nitro, nitroso-group, cyano group, repeatedly nitrilo, different sulfur nitro, OR, OC (O) R, OC (O) OR, OC (O) NRR', SO2R、SO3R、SO2NRR'、SR、NRR'、NRSO2NR'R"、NRSO2R'、NRSO3R', NRC (O) R', NRC (O) NR'R ", NRC (O) OR', NRC (N) NR'R ", C (O) R, C (O) OR or C (O) NRR' or RbWith Rc、RaWith Rb, or RcWith RdIt is O (CH together2)nO。
One or more methods as above, ReFor H, alkyl, thiazolinyl, alkynyl, ring base, heterocyclic radical, aryl, heteroaryl, halogen, nitro, nitroso-group, cyano group, repeatedly nitrilo, different sulfur nitro, OR, OC (O) R, OC (O) OR, OC (O) NRR', SO2R、SO3R、SO2NRR'、SR、NRR'、NRSO2NR'R"、NRSO2R'、NRSO3R', NRC (O) R', NRC (O) NR'R ", NRC (O) OR', NRC (N) NR'R ", C (O) R, C (O) OR or C (O) NRR'.
One or more methods as above, each R, R' and R " respectively H, alkyl, thiazolinyl, alkynyl, ring base, aryl, heteroaryl, ring base or heterocyclic radical, and n is 1,2,3,4 or 5.
One or more methods as above, described acylation reaction carries out not higher than 25 DEG C when.
On the other hand, the present invention also about the synthetic method of benzazolyl compounds shown in another kind of Formulas I, including:
I () lewis acid reacts in organic solvent with chlorine acyl compounds shown in formula III；
(ii) add starting indole shown in Formula II to react；
(iii) benzazolyl compounds is extracted.
One or more methods as above, wherein L1For C (O), RlFor the alkyl replaced through alkoxyl, ring base, heterocyclic radical, aryl or heteroaryl.
One or more methods as above, wherein RlFor 3,4,5-2,4,5-trimethoxyphenyl.
One or more methods as above, wherein the first acylation reaction catalyst is ethylmagnesium bromide EtMgBr and zinc chloride ZnCl2。
One or more methods as above, wherein the second acylation reaction catalyst or lewis acid are zinc chloride ZnCl2, boron trifluoride BF3, aluminum chloride AlCl3, titanium tetrachloride TiCl4, ferric chloride FeCl3, butter of tin SnCl4, Columbium pentachloride. NbCl5Or the fluoroform sulphonate of lanthanide series.
One or more methods as above, wherein organic solvent is dichloromethane CH2Cl2, chloroform CHCl3, tetrachloromethane CCl4, vinyl chloride C2Cl4Or trichloro ethylene C2HCl3。
One or more methods as above, described acylation reaction includes: ethylmagnesium bromide EtMgBr is added starting indole and zinc chloride ZnCl2With dichloromethane CH2Cl2Mixture in while, keep the temperature condition not higher than 25 DEG C.
One or more methods as above, wherein said acylation reaction farther includes: is added by chlorine acyl compounds while carrying out acylation reaction in mixture, keeps the temperature condition not higher than 25 DEG C.
One or more methods as above, add the second acylation reaction catalyst and include: by aluminum chloride AlCl3While adding in mixture, keeping the temperature condition not higher than 25 DEG C, the time that reacts was less than 5 hours.
One or more methods as above, by ethylmagnesium bromide EtMgBr, starting indole and zinc chloride ZnCl2With dichloromethane CH2Cl2Mixed mixture is cooled to the condition not higher than 25 DEG C.
One or more methods as above; wherein, described acylation reaction carries out at the temperature of the group formed selected from temperature below condition: not higher than 25 DEG C, not higher than 22.5 DEG C, not higher than 20 DEG C, not higher than 17.5 DEG C, not higher than 15 DEG C, not higher than 12.5 DEG C, not higher than 10 DEG C, not higher than 7.5 DEG C, not higher than 5 DEG C, not higher than 2.5 DEG C, not higher than 0 DEG C, not higher than-2.5 DEG C, not higher than-5 DEG C, not higher than-7.5 DEG C, not higher than-10 DEG C, not higher than-12.5 DEG C with not higher than-15 DEG C.
One or more methods as above, described acylation reaction carries out at the temperature of the group formed selected from temperature below condition: at 25 to-15 DEG C, 22.5 to-15 DEG C, 17.5 to-15 DEG C, at 15 to-15 DEG C, 12.5 to-12.5 DEG C, 10 to-10 DEG C, 7.5 to-7.5 DEG C, 5 to-5 DEG C, 2.5 to-2.5 DEG C, 25-15 DEG C, 15 to 12.5 DEG C, 12.5 to 10 DEG C, 10 to 7.5 DEG C, 7.5 to 5 DEG C, 5 to 2.5 DEG C, 2.5 to 0 DEG C, 0 to-2.5 DEG C ,-2.5 to-5 DEG C ,-5 to-10 DEG C ,-10 to-12.5 DEG C and-12.5 to-15 DEG C.
One or more methods as above, wherein the concentration of chlorine acyl compounds is 0.5-4Mol/L；Or 0.5-2Mol/L；Or 0.5-1.5Mol/L；Or 0.5-1.2Mol/L.
One or more methods as above ,-the L in starting indole shown in Formula II2-R2For blocking group, this blocking group is removed further after completion of the reaction.
One or more methods as above, wherein L2For SO2, R2For aryl.
One or more methods as above, the step of wherein said extraction benzazolyl compounds includes: change solvent or solvent exchange.
One or more methods as above, the step wherein changing solvent includes the organic layer after by extraction, is concentrated into dry and adds the second solvent；Wherein, benzazolyl compounds at the dissolubility of the second solvent lower than its dissolubility in the solvent of acylation reaction.
One or more methods as above, wherein dehydration adopts Na2S04, it includes Na2S04Join in the organic layer after extraction.
One or more methods as above; the step of wherein said solvent exchange includes the organic layer concentration after by extraction, adds the second solvent and heat the solvent to get rid of in acylation reaction and filter; wherein, benzazolyl compounds at the dissolubility of the second solvent lower than its dissolubility in the solvent of acylation reaction.
One or more methods as above, wherein farther include: be heated to reflux after the solvent got rid of in acylation reaction, and cooling is filtered, and washing.
One or more methods as above, are purified the benzazolyl compounds extracted after described acylation reaction further, and wherein purification step includes: dissolved in organic solvent by the thick product of benzazolyl compounds that acylation reaction is extracted；The mixture of benzazolyl compounds Yu organic solvent is heated to reflux；Control the temperature temperature range at the benzazolyl compounds intentionally got；It is cooled to mixture precipitate out critical state and filter；Wash and dry.
One or more methods as above, the thick product of benzazolyl compounds wherein extracted in acylation reaction adds activated carbon after dissolving in organic solvent；And after the mixture of benzazolyl compounds Yu organic solvent is heated to reflux, be filtered by kieselguhr.
Detailed description of the invention
For making the purpose of the embodiment of the present invention, technical scheme and advantage clearly, below in conjunction with the accompanying drawing in the embodiment of the present invention, technical scheme in the embodiment of the present invention is clearly and completely described, obviously, described embodiment is a part of embodiment of the present invention, rather than whole embodiments.Based on the embodiment in the present invention, the every other embodiment that those of ordinary skill in the art obtain under not making creative work premise, broadly fall into the scope of protection of the invention.
" benzazolyl compounds " in this paper includes the compound as shown in following formula I:
Wherein, L1For chemical bond, C (O), O, S, NR, SO2Or CH2；L2For chemical bond, C (O), O, S, NR, SO2Or CH2；RlFor alkyl, ring base, heterocyclic radical, aryl or heteroaryl；R2For H, aryl, heteroaryl, halogen, nitro, nitroso-group, cyano group, repeatedly nitrilo, different sulfur nitro, OR, OC (O) R, OC (O) OR, OC (O) NRR', SO2R、SO3R、SO2NRR'、SR、NRR'、NRSO2NR'R"、NRSO2R'、NRSO3R', NRC (O) R', NRC (O) NR'R ", NRC (O) OR', NRC (N) NR'R ", C (O) OR or C (O) NRR'；Wherein, each Ra、Rb、RcWith RdRespectively R, halogen, nitro, nitroso-group, cyano group, repeatedly nitrilo, different sulfur nitro, OR, OC (O) R, OC (O) OR, OC (O) NRR', SO2R、SO3R、SO2NRR'、SR、NRR'、NRSO2NR'R"、NRSO2R'、NRSO3R', NRC (O) R', NRC (O) NR'R ", NRC (O) OR', NRC (N) NR'R ", C (O) R, C (O) OR or C (O) NRR' or RbWith Rc、RaWith Rb, or RcWith RdIt is O (CH together2)nO；And ReFor H, alkyl, thiazolinyl, alkynyl, ring base, heterocyclic radical, aryl, heteroaryl, halogen, nitro, nitroso-group, cyano group, repeatedly nitrilo, different sulfur nitro, OR, OC (O) R, OC (O) OR, OC (O) NRR', SO2R、SO3R、SO2NRR'、SR、NRR'、NRSO2NR'R"、NRSO2R'、NRSO3R', NRC (O) R', NRC (O) NR'R ", NRC (O) OR', NRC (N) NR'R ", C (O) R, C (O) OR or C (O) NRR'；Each of which R, R' and R " respectively H, alkyl, thiazolinyl, alkynyl, ring base, aryl, heteroaryl, ring base or heterocyclic radical, and n is 1,2,3,4 or 5.
Alkyl presented herein, thiazolinyl, alkynyl, ring base, aryl, heteroaryl, ring base or heterocyclic radical include being substituted and being unsubstituted alkyl, thiazolinyl, alkynyl, ring base, aryl, heteroaryl, ring base or heterocyclic radical；Wherein term " being substituted " refers to that one or more identical or different substituent group replaces one or more hydrogen atoms, the example of substituent group includes but not limited to halogen, cyano group, nitro, hydroxyl, amido, sulfydryl, alkyl, thiazolinyl, alkynyl, ring base, aryl, heteroaryl, ring base, heterocyclic radical, alkoxyl, aryloxy group, alkane sulfonyl, virtue sulfonyl, alkylamino radical, aryl amine, di alkylamino group, diaryl-amine base, alkyl carbonyl, aromatic carbonyl, assorted aromatic carbonyl, alkane carboxyl, virtue carboxyl, assorted virtue carboxyl, alkoxy carbonyl group, aryloxy carbonyl, assorted aryloxy carbonyl, alkane urea groups, virtue urea groups, assorted urea groups, alkanamine formoxyl, arylamine formoxyl, assorted amine formyl.
" alkyl " presented herein includes the straight or branched alkyl of 1-6 carbon atom, includes but not limited to methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, n-pentyl.In the same manner, in this paper to " thiazolinyl " and " alkynyl " includes straight or branched thiazolinyl and the alkynyl of 2-6 carbon atom.
" aryl " presented herein includes 6-14 carbon atom and at least has the alkyl of an aromatic rings, includes but not limited to phenyl, naphthyl and pyrenyl." heteroaryl " presented herein includes 6-14 carbon atom and at least has the alkyl of an aromatic rings, the atom wherein forming aromatic rings includes at least one hetero atom, such as O, S, N etc., all the other are C atom, and it includes but not limited to furyl, pyrrole radicals, thienyl, oxazolyl, imidazole radicals, thiazolyl, pyridine radicals, pyrimidine radicals, quinazolyl and indyl.
" ring base " presented herein includes 4-14 carbon atom and at least has the alkyl of a circulus." heterocyclic radical " presented herein includes 4-14 carbon atom and at least has the alkyl of a circulus, and the atom wherein forming circulus includes at least one hetero atom, and such as O, S, N etc., all the other are C atom." ring base " and " heterocyclic radical " include but not limited to cyclohexyl, piperidyl, piperazinyl, morpholinyl, tetrahydro-1,4-thiazine base and 4-oxazepane base.
" benzazolyl compounds " in this paper includes the applying date in being incorporated herein in full and is December in 2002 12, whole benzazolyl compounds that denomination of invention is defined, discloses, describes or quotes in the United States Patent (USP) 6933316B2 for " benzazolyl compounds ".
It is below the example of benzazolyl compounds:
Compound 1:6-methoxyl group-3-(3,4,5-trimethoxybenzoy) indole；
Compound 2:6-methyl-3-(3,4,5-trimethoxybenzoy) indole；
The fluoro-3-of compound 3:6-(3,4,5-trimethoxybenzoy) indole；
The bromo-3-of compound 4:6-(3,4,5-trimethoxybenzoy) indole；
Compound 5:4,5,6-trimethoxy-3-(3,4,5-trimethoxybenzoy) indole；
Compound 6:5,6-dimethoxy-3-(3,4,5-trimethoxybenzoy) indole；
Compound 7:6-methoxyl group-2-methyl-3-(3,4,5-trimethoxybenzoy) indole；
Compound 8:6-ethyoxyl-3-(3,4,5-trimethoxybenzoy) indole；
Compound 9:7-methoxyl group-3-(3,4,5-trimethoxybenzoy) indole；
Compound 10:4-methoxyl group-3-(3,4,5-trimethoxybenzoy) indole；
Compound 11:5-methoxyl group-4-methyl-3-(3,4,5-trimethoxybenzoy) indole；
Compound 12:4,7-dimethoxy-3-(3,4,5-trimethoxybenzoy) indole；
Compound 13:4,6-dimethoxy-3-(3,4,5-trimethoxybenzoy) indole；
Compound 14:5,7-dimethoxy-3-(3,4,5-trimethoxybenzoy) indole；
Compound 15:6-hydroxyl-3-(3,4,5-trimethoxybenzoy) indole；
Compound 16:2-methyl-5-methoxyl group-3-(3,4,5-trimethoxybenzoy) indole；
Compound 17:6-methoxyl group-3-(3,4-Dimethoxybenzoyl) indole；And
Compound 18:5-methoxyl group-3-(3,4,5-trimethoxybenzoy) indole.
" starting indole " in this paper including: the compound as shown in Formula Il:
Wherein, L2、R2、Ra、Rb、Rc、RdWith ReDefinition identical with the definition in formula (I).
" chlorine acyl compounds " in this paper includes the compound shown in following formula III:
Wherein R1Definition identical with the definition in formula (I).
" acylation reaction " in this paper include all can hydrogen or other group by the reaction of acyl substituted, include but not limited to: acetylization reaction and grignard reaction (GrignardReaction)
" catalyst of acylation reaction " in this paper includes all catalyst that can be used in acylation reaction, includes but not limited to be applied to the catalyst of following reaction:
The example of the catalyst of acylation reaction includes: Grignard reagent (GrignardReagent), and described grignard reagent includes but not limited to: ethylmagnesium bromide EtMgBr, phenyl-magnesium-bromide PhMgBr, phenyl-magnesium-chloride PhMgCl etc..
" lewis acid (Lewisacid) " in this paper refers to electrophilic reagent or electron acceptor reagent, includes but not limited to: zinc chloride ZnCl2, boron trifluoride BF3, aluminum chloride AlCl3, titanium tetrachloride TiCl4, ferric chloride FeCl3, butter of tin SnCl4, Columbium pentachloride. NbCl5And the fluoroform sulphonate etc. of lanthanide series.
" organic solvent " in this paper refers to the solvent that Organic substance is medium, includes but not limited to all organic solvents that can be used in as above reacting (1).The example of organic solvent includes: dichloromethane CH2Cl2, chloroform CHCl3, tetrachloromethane CCl4, vinyl chloride C2Cl4, trichloro ethylene C2HCl3Deng.
Being appreciated by by those skilled in the art, benzazolyl compounds can via approach synthesis such as disclosed below:
1. acylation reaction:
And
2. substitution reaction:
Or,
Each example of the present invention more pays close attention to the part of the coupled reaction as described by above-mentioned reaction equation (1)；And the substitution reaction part such as reaction equation (2) or (3) can be December in 2002 12 by the applying date in being such as incorporated herein in full, the mode as known in the art that denomination of invention is defined, discloses, describes or quotes in the United States Patent (USP) 6933316B2 for " benzazolyl compounds " is implemented.
Starting indole can also first and after sulfonamide agent (sulfonamidatingagent) forms blocking group; carry out acylation reaction; disconnecting the N-S key in sulfoamido again, the benzazolyl compounds such as formulas below (4) to obtain the present invention is disclosed:
" sulfonamide agent " in this paper refers to the reagent of amido effect formation sulfoamido, to include but not limited to alkane sulfuryl halide, such as mesyl chloride, benzene sulfonyl chloride and paratoluensulfonyl chloride etc..Carry out sulfuryl amine and can add phase transfer catalyst." phase transfer catalyst " in this paper be can help reactant from a phase transfer to can react another quite, thus accelerating a class catalyst of outphasing system reaction rate, include but not limited to quaternary ammonium salt, such as benzyltriethylammoinium chloride (TEBA), tetrabutyl ammonium bromide (Bu4NBr), tetrabutylammonium chloride (Bu4NCl), 4-butyl ammonium hydrogen sulfate (TBAB) and tri-n-octyl methyl ammonium chloride.
" blocking group " in this paper refers to for protecting particular functional base to avoid round reaction to destroy in organic synthesis, and the group that question response is sloughed after completing again includes but not limited to alkane sulphonyl, such as methylsulfonyl, benzene sulfonyl and tolysulfonyl etc..
According to one embodiment of present invention, the method for synthesis of indole compound includes: when the first catalyst (such as Grignard reagent and first via Lewis acid) so that the starting indole in solvent and chlorine acyl compounds carry out acylation reaction；Add the second catalyst (such as the second lewis acid)；Extract；And extraction benzazolyl compounds；Wherein said acylation reaction carries out not higher than 25 DEG C when.
According to an example of the present invention, adopt ethylmagnesium bromide EtMgBr and zinc chloride ZnCl2Catalyst combination, the method for its synthesis of indole compound includes: ethylmagnesium bromide EtMgBr is added starting indole and zinc chloride ZnCl2Mixture in.According to an example of the present invention, adopt phenyl-magnesium-bromide and ferric chloride FeCl3Catalyst combination.
According to one embodiment of present invention, ethylmagnesium bromide EtMgBr and zinc chloride ZnCl is adopted2Catalyst and dichloromethane CH2Cl2The combination of organic solvent, the method for its synthesis of indole compound includes: ethylmagnesium bromide EtMgBr is added starting indole and zinc chloride ZnCl2With dichloromethane CH2Cl2Mixture in；Chlorine acyl compounds is added in mixture and carries out acylation reaction；By such as aluminum chloride AlCl3The second lewis acid add in mixture；Extract mixture；And extraction benzazolyl compounds, thus obtaining the benzazolyl compounds of target, wherein said acylation reaction carries out not higher than 25 DEG C when.
According to one embodiment of present invention, the method for its synthesis of indole compound keeps the temperature condition not higher than 25 DEG C while including adding in mixture chlorine acyl compounds and carrying out acylation reaction.
According to one embodiment of present invention, the method for its synthesis of indole compound includes aluminum chloride AlCl3While adding in mixture, keep the temperature condition not higher than 25 DEG C.
According to one embodiment of present invention, the method for its synthesis of indole compound includes ethylmagnesium bromide EtMgBr is added starting indole and zinc chloride ZnCl2With dichloromethane CH2Cl2Mixture in while, keep the temperature condition not higher than 25 DEG C.
According to one embodiment of present invention, the method for its synthesis of indole compound includes: by ethylmagnesium bromide EtMgBr, starting indole and zinc chloride ZnCl2With dichloromethane CH2Cl2Mixed mixture is cooled to the condition not higher than 25 DEG C.
Owing to acylation reaction itself is exothermic reaction, controlling if or not temperature when at room temperature carrying out, reaction temperature will quickly more than 25 DEG C.Usual cognitive according to those skilled in the art, at high temperature advantageously in accelerating acylation reaction process, reduces the time of reaction, for scale production advantageously.But, it was unexpectedly determined that inventors herein have recognized that the speed of acylation reaction is faster lower than 25 DEG C when.
Embodiment according to the present invention, acylation reaction preferably not higher than not higher than 25 DEG C, not higher than 22.5 DEG C, not higher than 20 DEG C, not higher than 17.5 DEG C, not higher than 15 DEG C, 12.5 DEG C, carry out under temperature conditions not higher than 10 DEG C, not higher than 7.5 DEG C, not higher than 5 DEG C, not higher than 2.5 DEG C, not higher than 0 DEG C, not higher than-2.5 DEG C, not higher than-5 DEG C, not higher than-7.5 DEG C, not higher than-10 DEG C, not higher than-12.5 DEG C or not higher than-15 DEG C.Embodiment according to the present invention, acylation reaction is preferably to be carried out under the temperature conditions 25 to-15 DEG C, 22.5 to-15 DEG C, 17.5 to-15 DEG C, 15 to-15 DEG C, 12.5 to-12.5 DEG C, 10 to-10 DEG C, 7.5 to-7.5 DEG C, 5 to-5 DEG C, 2.5 to-2.5 DEG C, 25-15 DEG C, 15 to 12.5 DEG C, 12.5 to 10 DEG C, 10 to 7.5 DEG C, 7.5 to 5 DEG C, 5 to 2.5 DEG C, 2.5 to 0 DEG C, 0 to-2.5 DEG C ,-2.5 to-5 DEG C ,-5 to-10 DEG C ,-10 to-12.5 DEG C or-12.5 to-15 DEG C.
According to one embodiment of present invention, the method for synthesis of indole compound includes: lewis acid and chlorine acyl compounds are reacted in organic solvent；Add starting indole to react；Extract benzazolyl compounds.
According to one embodiment of present invention, starting indole is through benzene sulfonyl chloride and Bu4After NBr acts in the basic conditions, then react in organic solvent with lewis acid and chlorine acyl compounds；Disconnect N-S key-like in the basic conditions to become to be intended to the benzazolyl compounds of synthesis；Extract benzazolyl compounds.
Another concentration range finding to be in that chlorine acyl compounds of present inventor.According to an example of the present invention, the concentration of chlorine acyl compounds be 0.5-4Mol/L advantageously；Or 0.5-2Mol/L is advantageously；Or 0.5-1.5Mol/L is advantageously；Or 0.5-1.2Mol/L is advantageously.This discovery is also different with the usual cognition of this area.It is generally believed that the concentration of reactant is more high more is conducive to the carrying out reacted.But, it is found by the applicant that for the acylation reaction of the application, the concentration of chlorine acyl compounds is reacted in above-mentioned scope and is carried out faster, also more thorough, rather than the concentration of chlorine acyl compounds is more high more good.
According to one embodiment of present invention, the extraction step in the method for synthesis of indole compound includes extracting with water.Extraction step includes extracting 2 times, 3 times, 4 times or 5 times.Extraction step farther includes: wash organic layer after extraction with water.According to an example of the present invention, extraction step includes the mixture after by acylation reaction and is poured into water, or adds water in the mixture after acylation reaction.
According to one embodiment of present invention, the step extracting benzazolyl compounds in the method for synthesis of indole compound includes: change solvent and filtration.According to an example of the present invention, the step changing solvent includes the organic layer after by extraction, is concentrated into dry and adds the second solvent.Wherein, benzazolyl compounds at the dissolubility of the second solvent lower than its dissolubility in the solvent of acylation reaction.The step filtered includes cooling and filters.Wherein, the step of dehydration adopts Na2S04, it includes Na2S04Join in the organic layer after extraction.But, in large-scale production, aforesaid way is slightly disliked loaded down with trivial details and is concentrated into and dry is difficult to control to aborning.
According to an example of the present invention, the step changing solvent includes solvent exchange.The step of solvent exchange includes the organic layer concentration after by extraction, adds the second solvent and heat the solvent to get rid of in acylation reaction and filter.Wherein, benzazolyl compounds at the dissolubility of the second solvent lower than its dissolubility in the solvent of acylation reaction.The step filtered includes cooling and filters.It should be noted that the step not comprising dehydration in this example, because water can be removed in the step of solvent exchange；Further, the present embodiment does not include the unmanageable dry step that is concentrated into yet, operate more simple.
According to an example of the present invention, the step of solvent exchange farther includes: be heated to reflux after the solvent got rid of in acylation reaction.Many undesired by-products can be removed by heating this step under reflux.After step of heating for reflux, other impurity except major impurity in benzazolyl compounds are greatly reduced.This result is beat all.
According to one embodiment of present invention, the method for synthesis of indole compound farther includes decolorization process.Less desirable dark-coloured waste material can be removed, thus improving the outward appearance of benzazolyl compounds by decolorization process.Decolorization process can carry out before solvent changes step.Decolorization process can also carry out after dehydration.It should be noted that, loss of yield should be avoided in decolorization process as best one can.United States Patent (USP) 6933316B2 adopts Na2S04Combination with silica gel is decoloured.But, this method can bring the loss of yield of about 10-15%.According to an example of the present invention, decolorization process includes the combination utilizing activated carbon and kieselguhr (Celite, also referred to as celite).The example of decolorization process specifically includes in the organic layer after activated carbon is added into extraction, then filters then through kieselguhr.This mode can largely reduce the loss of productivity.By activated carbon application, in decolorization process and to obtain superior technique effect be beat all.General viewpoint is thought, activated carbon is higher for the trapping ability of lipophilic compound.Owing to benzazolyl compounds is lipophilic, the utility theory of activated carbon can bring bigger loss of yield.But, inventors herein have recognized that, the application of activated carbon is prevented from the loss of yield owing to being caused by filtered through silica gel, obtains superior technique effect.
According to an example of the present invention, farther include the benzazolyl compounds after washing and filtering.A preferred example according to the present invention, this washing step can adopt EA or MeOH (methanol)/H2The mixture washing of O=2/1.Compared to other cleaning solvent, MeOH (methanol)/H2The mixture washing of O=2/1 can be substantially improved the outward appearance of benzazolyl compounds.Further, then carrying out recrystallization one or more times, and use more activated carbon wherein, the outward appearance of benzazolyl compounds can be improved further.
According to one embodiment of present invention, the benzazolyl compounds that the benzazolyl compounds synthetic method of the present invention still further comprises extracting after acylation reaction is purified.
The benzazolyl compounds obtained by acylation reaction is a kind of thick product, and also protection has other impurity a number of.Therefore, the method for the present invention further comprises the step of purification.Inventors herein have recognized that the impurity of benzazolyl compounds is often the isomer of benzazolyl compounds, for instance the acylation reaction on C-2 position.
According to one embodiment of present invention, the step of purification includes: dissolved in organic solvent by the thick product of benzazolyl compounds that acylation reaction is extracted；The mixture of benzazolyl compounds Yu organic solvent is heated to reflux；Mixture is cooled down and filters；Wash and dry, thus obtaining the smart product of benzazolyl compounds.According to an example of the present invention, it is possible to the smart product for benzazolyl compounds derived above carries out secondarily purified in the same way.Another example according to the present invention, is dried in a vacuum.According to an example of the present invention, the isomer of different benzazolyl compounds is likely to be of different Precipitation Temperature.Therefore, the step of purification includes the temperature range controlling temperature at the benzazolyl compounds intentionally got, thus being separated with its isomer by benzazolyl compounds.
The selection of organic solvent has great significance for the purification step of recrystallization.According to an example of the present invention, organic solvent is the mixture of EA or EA and MeOH.Such as, the isomer of the benzazolyl compounds of 5-10% can be removed using the mixture of EA and MeOH as solvent, but the purity of the smart product of benzazolyl compounds can lower than 90%.And organic solvent is when being EA, the purity of the smart product of benzazolyl compounds can more than 90%.
According to an example of the present invention, the step of purification includes: when being cooled down by mixture, is first cooled to the precipitation critical state of benzazolyl compounds, i.e. cloud point, and stirs a period of time；Then it is being cooled to Precipitation Temperature.Present inventor is it has surprisingly been found that be cooled to cloud point and stir the mode of a period of time and be to ensure that the key that benzazolyl compounds precipitates out completely.Thus, it is thus achieved that the purity of smart product of benzazolyl compounds can more than 99%.
According to an example of the present invention, purification step also includes decolorization process.Specifically, activated carbon can be added between recrystallization to trap less desirable yellow, improve the outward appearance of product.According to an example of the present invention, after the thick product of benzazolyl compounds of acylation reaction extraction dissolves in organic solvent, add activated carbon；And after the mixture of benzazolyl compounds Yu organic solvent is heated to reflux, be filtered by kieselguhr.
According to an example of the present invention, purification step also includes washing step.A preferred example according to the present invention, this washing step can adopt EA or MeOH (methanol)/H2The mixture washing of O=2/1.Compared to other cleaning solvent, MeOH (methanol)/H2The mixture washing of O=2/1 can be substantially improved the outward appearance of benzazolyl compounds.
Embodiment (one)
It is the anticancer compound with resisting mitosis activity very with prospect that 6-methoxyl group-3-(3,4,5-trimethoxybenzoy) indole (is called for short SCB01A).
The structure of SCB01A is such as shown in formula A:
SCB01A
C19H19NO5
MW:341.36
Reference examples 1:
Method described by United States Patent (USP) 6933316B2, scales up the amount participating in the reactant of acetylization reaction；Further, the technique after amplifying according to the usual skill comparative example of this area is adjusted, as the reference examples of the synthetic method of the present invention.
Specific as follows: at room temperature, by 6-methoxy-Indole (109.0g, 1.0eq., 1.0wt.), ZnCl2(201.9g, 2.0eq., 1.85wt.) and CH2Cl2(1450ml, 13.3vol.) joins in reactor.It is slowly added to 3.0M ethylmagnesium bromide EtMgBr (321ml, 1.3eq., 3.0vol.), and stirring is not less than 1 hour.By CH2Cl23,4,5-trimethoxy-benzoyl chlorides (222.1g, 2.0wt.) in (450ml, 4.1vol.) add to mixture, and stirring is not less than 1 hour.By AlCl3(98.7g, 1.0eq., 0.9wt.) adds to mixture by part, and monitors the carrying out of reaction.It was found that, stirring just can make reaction carry out relatively fully when being not less than 12 hours.
Pour the mixture into and water (1200.0g, 11.0vol.) terminates reaction.By aqueous phase CH2Cl2(200ml, 1.83vol.) extracting twice；Again organic layers with water (500ml, 4.6vol.) is washed twice.Aqueous phase with saturated NaC1 (aq) (740ml, 6.8vol.) washing and is abandoned by organic layer.By Na2S04(200.0g, 1.8wt.) adds to organic layer, then by mixture by silica gel (150g, 1.4wt.) and Na2S04(100.0g,0.9wt.)；Concentrate the filtrate to again dry.According to the method described above, the thick SCB01A productivity obtained is about 45-55%.
The example 1 of the present invention:
At room temperature, in reactor, 6-methoxy-Indole (45.0g, 1.0eq., 1.0wt.), ZnCl are loaded2(83.3g, 2.0eq., 1.85wt.) and CH2Cl2(620ml,13.7vol.).Mixture is cooled to lower than 15 DEG C, and is slowly added to 3.0MEtMgBr (132.5ml, 1.3eq., 2.9vol.), maintain temperature at-5 to 5 DEG C simultaneously.Stir the mixture for being not less than 1h, maintain temperature at-5 to 5 DEG C simultaneously.
By CH2Cl23,4,5-trimethoxy-benzoyl chlorides (91.7g, 1.3eq., 2.0wt.) in (415ml, 9.2vol.) add to mixture, are maintained with temperature lower than-5 to 5 DEG C.Stir the mixture for being not less than 1h, simultaneously maintain temperature lower than-5 to 5 DEG C.
By AlCl3(40.7g, 1.0eq., 0.9wt.) adds to mixture by part, is maintained with temperature lower than 15 DEG C.Utilize HPLC monitoring reaction course, it was surprisingly found that reaction was basically completed within 2 hours.
Water (495.0g, 11.0wt.) is added to mixture, then abandons water layer.Wash organic layer with water (495.0g, 11wt.), then water layer is abandoned.Activated carbon (7.2g, 0.16wt.) is added to organic layer, and stirs mixture.Then, mixture is filtered by kieselguhr (Celite, also referred to as celite) and uses dichloromethane CH2Cl2(225ml, 5vol.) washs.
Filtrate is concentrated, and adds EA (ethyl acetate) (450ml, 10vol.) and carry out solvent exchange.Heating blends also keeps the temperature boiling point lower than SCB01A, until the density that the density of distillate is equal to EA.Make mixture maintain about 5vol., and stir under reflux.Mixture is cooled down, and filtering mixt, then use MeOH/H2O=2/1 (270ml, 6vol.) washs.Being dried in a vacuum at being not more than 50 DEG C by wet cake, thus providing thick SCB01A, its productivity is 60-75%.
The example 2 of the present invention:
Except temperature controls at 5-10 DEG C, all the other are identical with the experiment condition in example 1.In example 2, AlCl3About 2 hours of rear stirring, the productivity adding SCB01A is approximately 55-70%.
The example 3 of the present invention:
Except temperature controls at 15-25 DEG C, all the other are identical with the experiment condition in example 1.In example 3, AlCl3About 5 hours of rear stirring, the productivity of SCB01A is approximately 50-60%.
The example 4 of the present invention:
In applicable reactor, load thick SCB01A (130.0g, 1.0wt.), EA (700ml, 5.4vol.) and MeOH (50ml, 0.4vol.) that example 1 extracts, be maintained with temperature at 20-30 DEG C.Heat the mixture to backflow and stirring is not less than 1 hour.Mixture is cooled to 20-30 DEG C and filters.With EA (200ml, 1.5vol.) washing and being dried in a vacuum at being not more than 50 DEG C by wet cake, thus providing SCB01A (80.0g), purity is less than 90%.
The example 5 of the present invention:
In applicable reactor, load thick SCB01A (55.0g, 1.0wt.) and EA (825ml, 15vol.), be maintained with temperature at 20-30 DEG C.Heat the mixture to backflow and stir until all dissolving.
Add activated carbon DarcoKB (7.2g, 0.16wt.), and mixture is stirred under reflux.Mixture is filtered by kieselguhr and is washed by wet cake EA (165ml, 3vol.).Concentrate the filtrate to～825ml (15vol.), and stir until all dissolving under reflux.
Mixture is cooled to 60-65 DEG C (that is: cloud point), and stirs a period of time at such a temperature.Mixture is cooled to about 30 DEG C and filter.By wet cake MeOH/H2O=2/1 (330ml, 6vol.) washs.Being dried in a vacuum at no more than 50 DEG C by wet cake, to provide SCB01A, purity is approximately 99%.
The example 6 of the present invention
Loading thick SCB01A (1.473kg) and EA (19.90kg) in applicable reactor, heated and stirred is cooled back to about 10 DEG C to being completely dissolved.
Add activated carbon DarcoKB (0.147kg), and mixture heating, stirring are being cooled to about 10 DEG C.Mixture is filtered by kieselguhr and is washed by wet cake EA.Filtrate is concentrated and stirs until all dissolving under reflux.
Mixture is cooled to 60-65 DEG C (that is: cloud point), and stirs a period of time at such a temperature so that the precipitation completely of SCB01A.Mixture is cooled to about 30 DEG C and filter.By wet cake MeOH/H2O=2/1 washs 3 times.Being dried in a vacuum at no more than 50 DEG C by wet cake, to provide SCB01A, purity is approximately 99.89%.
The example 7 of the present invention
Loading thick SCB01A (1.402kg) and EA (18.96kg) in applicable reactor, heated and stirred is cooled back to about 10 DEG C to being completely dissolved.
Add activated carbon DarcoKB (0.140kg), and mixture is stirred under reflux.Mixture is filtered by kieselguhr and is washed by wet cake EA.Filtrate is concentrated and stirs until all dissolving under reflux.
Mixture is cooled to 60-65 DEG C (that is: cloud point), and stirs a period of time at such a temperature so that the precipitation completely of SCB01A.Mixture is cooled to about 30 DEG C and filter.By wet cake MeOH/H2O=2/1 washs 2 times.Being dried in a vacuum at no more than 50 DEG C by wet cake, to provide SCB01A, purity is approximately 99.7%.
The example 8 of the present invention
At room temperature, 3 minutes are lasted by dry for EtMgBr (3mL, 3.0M solution is in ether) addition CH2Cl2(40mL), 6-methoxy-Indole (1g, 6.8mmol) and anhydrous ZnCl2The mixture of (1.85g, 13.6mmol).By suspension agitation 2 hours, and last 5 minutes subsequently and be added dropwise over 3,4,5-trimethoxy-benzoyl chlorides (1.88g, 8.15mmol) and be dissolved in dry CH2Cl2(40mL) solution, is subsequently added AlCl3(1.09g,8.17mmol).Reactant mixture is stirred 4 hours, is maintained with temperature lower than 25 DEG C.React and terminate and with CH through add water (80mL)2Cl2(80mL) extract.The organic layer through merging is washed, through Na with 1NNaOH (80mL) and water (80mLx2)2SO4Dry, produce SCB01A (1.48g, 64%) with silica gel column chromatography purification (purging with liquid: EtOAc/n-hexane1:1 is 3:2 thereafter).Sample is analyzed from the preparation of methanol recrystallization.Wherein, activated carbon and diatomaceous combination is used to carry out the decolorization process of benzazolyl compounds.
mp185.5-185.8℃。1HNMR(200MHz,DMSO-d6): δ 3.77 (s, 3H), 3.82 (s, 3H), 3.87 (s, 6H), 6.89 (dd, J=8.8,2Hz, 1H), 7.01 (d, J=1.8Hz, 1H), 7.09 (s, 2H), 7.99 (s, 1H), 8.12 (d, J=8.8Hz, 1H), (11.86 br, 1H, NH).13CNMR(50MHz,DMSO-d6):δ55.7,56.4,60.6,95.6,106.4,112.1,115.4,120.8,122.6,135.1,136.2,138.1,140.4,153.0,157.0,189.3。MS(EI)m/z342(MH+)。C19H19NO5Analytical calculation value: C66.85, H5.61, N4.10；Experiment value: C66.75, H5.62, N4.10.
The example 9 of the present invention
At room temperature by AlCl3(363mg, 2.72mmol) adds 3,4,5-trimethoxy-benzoyl chloride (470mg, 2.04mmol) and is dissolved in dry CH2Cl2(10mL) solution, and stir the mixture for 20 minutes.It is added dropwise over 6-methoxy-Indole (250mg, 1.7mmol) and is dissolved in dry CH2Cl2(10mL) solution, reactant mixture at room temperature stirs 2 hours, reacts and terminates through add water (20mL).Aqueous layer is with CH2Cl2(20mLx2) extract.The organic layer merged washs with 1NNaOH (30mL) and saline (30mLx2), through Na2SO4Dry, and concentrating under reduced pressure.Gained residue produces 6-methoxyl group-3-(3,4,5-trimethoxybenzoy) indole (146mg, 25%) with silica gel column chromatography purification (purging with liquid: EtOAc/n-hexane1:1).Wherein, activated carbon and diatomaceous combination is used to carry out the decolorization process of benzazolyl compounds.
Embodiment (two)
5-methoxyl group-3-(3,4,5-trimethoxybenzoy) indole
The example 1 of the present invention
At room temperature, 3 minutes are lasted by dry for EtMgBr (3mL, 3.0M solution is in ether) addition CH2Cl2(40mL), 5-methoxy-Indole (1g, 6.8mmol) and anhydrous ZnCl2The mixture of (1.85g, 13.6mmol).By suspension agitation 2 hours, and last 5 minutes subsequently and be added dropwise over 3,4,5-trimethoxy-benzoyl chlorides (1.88g, 8.15mmol) and be dissolved in dry CH2Cl2(40mL) solution, is subsequently added AlCl3(1.09g,8.17mmol).Reactant mixture is stirred 4 hours, is maintained with temperature lower than 25 DEG C.React and terminate and with CH through add water (80mL)2Cl2(80mL) extract.The organic layer through merging is washed, through Na with 1NNaOH (80mL) and water (80mLx2)2SO4Dry, produce 5-methoxyl group-3-(3,4,5-trimethoxybenzoy) indole (0.69g, 30%) with silica gel column chromatography purification (purging with liquid: EtOAc/n-hexane1:1 is 3:2 thereafter).Sample is analyzed from the preparation of methanol recrystallization.Wherein, activated carbon and diatomaceous combination is used to carry out the decolorization process of benzazolyl compounds.
mp194.2-194.7℃。1HNMR(200MHz,CDCl3): δ 3.91 (s, 9H), 3.94 (s, 3H), 6.98 (dd, J=8.8,2.2Hz, 1H), 7.11 (s, 2H), 7.35 (d, J=9.0Hz, 1H), 7.70 (d, J=3.2Hz, 1H), 7.93 (d, J=2.4Hz, 1H), 8.87 (br, 1H, NH).13CNMR(50MHz,CDCl3):δ55.8,56.3,61.0,103.5,106.3,112.2,114.7,116.7,127.3,131.2,133.6,136.0,140.8,153.0,156.5,190.6。MS(EI)m/z342(MH+)。C19H19NO5Analytical calculation value: C66.85, H5.61, N4.10；Experiment value: C66.8, H5.65, N4.11.
The example 2 of the present invention
At room temperature by AlCl3(363mg, 2.72mmol) adds 3,4,5-trimethoxy-benzoyl chloride (470mg, 2.04mmol) and is dissolved in dry CH2Cl2(10mL) solution, and stir the mixture for 20 minutes.It is added dropwise over 5-methoxy-Indole (250mg, 1.7mmol) and is dissolved in dry CH2Cl2(10mL) solution, reactant mixture at room temperature stirs 2 hours, reacts and terminates through add water (20mL).Aqueous layer is with CH2Cl2(20mLx2) extract.The organic layer merged washs with 1NNaOH (30mL) and saline (30mLx2), through Na2SO4Dry, and concentrating under reduced pressure.Gained residue adds diethyl ether and grinds, and solid is through being filtrated to get 5-methoxyl group-3-(3,4, the 5-trimethoxybenzoy) indole of 260mg.Filtrate is volatilized, residue adds diethyl ether/and methanol grinds.Solid collected by filtration is to obtain extra 5-methoxyl group-3-(3,4,5-trimethoxybenzoy) indole (45mg).Compound gross production rate is 53% (305mg).Wherein, activated carbon and diatomaceous combination is used to carry out the decolorization process of benzazolyl compounds.
Embodiment (three)
4-methoxyl group-3-(3,4,5-trimethoxybenzoy) indole
The example 1 of the present invention
At room temperature, 3 minutes are lasted by dry for EtMgBr (3mL, 3.0M solution is in ether) addition CH2Cl2(40mL), 4-methoxy-Indole (1g, 6.8mmol) and anhydrous ZnCl2The mixture of (1.85g, 13.6mmol).By suspension agitation 2 hours, and last 5 minutes subsequently and be added dropwise over 3,4,5-trimethoxy-benzoyl chlorides (1.88g, 8.15mmol) and be dissolved in dry CH2Cl2(40mL) solution, is subsequently added AlCl3(1.09g,8.17mmol).Reactant mixture is stirred 4 hours, is maintained with temperature lower than 25 DEG C.React and terminate through add water (80mL).Filter precipitation and obtain 4-methoxyl group-3-(3,4,5-trimethoxybenzoy) indole of 1.81g with water washing.Biphase filtrate is separated, and aqueous phase is with CH2Cl2(80mL) extract.The organic layer through merging is washed, through Na with 1NNaOH (80mL) and water (80mLx2)2SO4Dry, and concentrating under reduced pressure.Gained residue adds methanol and grinds, and solid is through being filtrated to get extra 4-methoxyl group-3-(3,4,5-trimethoxybenzoy) indole (0.23g).Compound gross production rate is 88% (2.04g).Sample is analyzed from the preparation of methanol recrystallization.Wherein, activated carbon and diatomaceous combination is used to carry out the decolorization process of benzazolyl compounds.
mp232.9-233.2℃。1HNMR(200MHz,DMSO-d6): δ 3.65 (s, 3H), 3.76 (s, 3H), 6.57 (d, J=6.6Hz, 1H), 7.06 (s, 4H), 7.62 (s, 1H), 11.74 (br, 1H, NH).13CNMR(50MHz,DMSO-d6):δ55.3,60.5,61.0,102.2,105.6,107.3,116.1,116.4,124.1,131.9,135.8,138.7,141.1,152.6,153.9,188.9。MS(EI)m/z342(MH+)。C19H19NO5Analytical calculation value: C66.85, H5.61, N4.10；Experiment value: C66.83, H5.63, N4.10.
Embodiment (four)
The fluoro-3-of 6-(3,4,5-trimethoxybenzoy) indole
The example 1 of the present invention
At room temperature, 3 minutes are lasted by dry for EtMgBr (3mL, 3.0M solution is in ether) addition CH2Cl2(40mL), the fluoro-indole of 6-(0.92g, 6.8mmol) and anhydrous ZnCl2The mixture of (1.85g, 13.6mmol).By suspension agitation 2 hours, and last 5 minutes subsequently and be added dropwise over 3,4,5-trimethoxy-benzoyl chlorides (1.88g, 8.15mmol) and be dissolved in dry CH2Cl2(40mL) solution, is subsequently added AlCl3(1.09g,8.17mmol).Reactant mixture is stirred 4 hours, is maintained with temperature lower than 25 DEG C.React and terminate through add water (80mL).Filter precipitation and obtain the fluoro-3-of 6-(3,4,5-trimethoxybenzoy) indole (2.14g, 96%) with water washing.Sample is analyzed from the preparation of methanol recrystallization.Wherein, activated carbon and diatomaceous combination is used to carry out the decolorization process of benzazolyl compounds.
mp217.3-217.8℃。1HNMR(200MHz,DMSO-d6): δ 3.75 (s, 3H), 3.84 (s, 6H), 7.08-7.13 (m, 3H), 7.28 (dd, J=9.5,2.1Hz, 1H), 8.11 (d, J=3Hz, 1H), 8.21 (d, J=8.7Hz, 5.7Hz, 1H), (12.1 br, 1H, NH).13CNMR(50MHz,DMSO-d6):δ56.4,60.6,98.6,99.1,106.5,110.4,110.9,115.2,123.0,123.2, 123.5,135.9,136.7,137.1,137.4,140.6,153.1,157.5,162.2,189.3。MS(EI)m/z330(MH+)。C18H16FNO4Analytical calculation value: C65.65, H4.90, N4.25；Experiment value: C65.71, H4.98, N4.26.
The example 2 of the present invention
At room temperature, by AlCl3(380mg, 2.85mmol) adds 3,4,5-trimethoxy-benzoyl chloride (490mg, 2.12mmol) and is dissolved in dry CH2Cl2(20mL) solution, and stir the mixture for 20 minutes.Adding 6-fluoro indole (230mg, 1.7mmol), reactant mixture at room temperature stirs 2 hours, reacts and terminates through add water (20mL).Add CH2Cl2(20mL), it is separated.Aqueous layer is with CH2Cl2(20mL) extract.The organic layer merged washs with 1NNaOH (30mL) and saline (30mLx2), through Na2SO4Dry, and concentrating under reduced pressure.Gained residue adds methanol and grinds, and solid is through the 6-being filtrated to get 353mg fluoro-3-(3,4,5-trimethoxybenzoy) indole.Filtrate being volatilized, residue adds diethyl ether and grinds.Solid collected by filtration is to obtain the fluoro-3-of extra 6-(3,4,5-trimethoxybenzoy) indole (52mg).Compound gross production rate is 72% (405mg).Wherein, activated carbon and diatomaceous combination is used to carry out the decolorization process of benzazolyl compounds.
Embodiment (five)
2-methyl-5-methoxyl group-3-(3,4,5-trimethoxybenzoy) indole
The example 1 of the present invention
At room temperature, 3 minutes are lasted by dry for EtMgBr (0.75mL, 3.0M solution is in ether) addition CH2Cl2(10mL), 2-methyl-5-Methoxv-indole (274mg, 1.7mmol) and anhydrous ZnCl2The mixture of (463mg, 3.4mmol).By suspension agitation 1 hour, and last 5 minutes subsequently and be added dropwise over 3,4,5-trimethoxy-benzoyl chlorides (470mg, 2.04mmol) and be dissolved in dry CH2Cl2(20mL) solution, is subsequently added AlCl3(272mg,2.04mmol).Reactant mixture is stirred 5 hours, is maintained with temperature lower than 25 DEG C.React and terminate and with CH through add water (20mL)2Cl2(20mLx2) extract.The organic layer through merging is washed, through Na with 1NNaOH (30mL) and water (30mLx2)2SO4Dry, produce 2-methyl-5-methoxyl group-3-(3,4,5-trimethoxybenzoy) indole (289mg, 48%) with silica gel column chromatography purification (purging with liquid: EtOAc/n-hexane2:3).Sample is analyzed from the preparation of methanol recrystallization.Wherein, activated carbon and diatomaceous combination is used to carry out the decolorization process of benzazolyl compounds.
mp162.2-162.8℃。1HNMR(200MHz,DMSO-d6): δ 2.37 (s, 3H), 3.66 (s, 3H), 3.76 (s, 3H), 3.78 (s, 6H), 6.78 (dd, J=8.8,2.2Hz, 1H), 6.93 (s, 2H), 7.00 (d, J=2.2,1H), 7.29 (d, J=8.6Hz, 1H), (11.83 br, 1H, NH).13CNMR(50MHz,DMSO-d6):δ14.9,55.5,56.4,60.7,103.2,106.0,111.7,112.3,112.8,128.6,130.4,137.4,140.2,145.0,153.1,155.1,190.0。MS(EI)m/z356(MH+)。C20H21NO5Analytical calculation value: C67.59, H5.96, N3.94；Experiment value: C67.38, H5.99, N3.90.
Embodiment (six)
6-methoxyl group-3-(3,4-Dimethoxybenzoyl) indole
The example 1 of the present invention
At room temperature, 3 minutes are lasted by dry for EtMgBr (3mL, 3.0M solution is in ether) addition CH2Cl2(40mL), 6-methoxy-Indole (1g, 6.8mmol) and anhydrous ZnCl2The mixture of (1.85g, 13.6mmol).By suspension agitation 2 hours, and last 5 minutes subsequently and be added dropwise over 3,4-dimethoxy-benzoyl chlorides (1.64g, 8.17mmol) and be dissolved in dry CH2Cl2(40mL) solution, is subsequently added AlCl3(1.09g,8.17mmol).Reactant mixture is stirred 4 hours, is maintained with temperature lower than 25 DEG C.React and terminate through add water (80mL).Filter precipitation and obtain 6-methoxyl group-3-(3,4-Dimethoxybenzoyl) indole of 0.86g with water washing.Biphase filtrate is separated, and aqueous phase is with CH2Cl2(80mL) extract.The organic layer through merging is washed, through Na with 1NNaOH (80mL) and water (80mLx2)2SO4Dry, and concentrating under reduced pressure.Gained residue adds methanol and grinds, and solid is through being filtrated to get extra 6-methoxyl group-3-(3,4-Dimethoxybenzoyl) indole.Compound gross production rate is 52% (1.1g).Sample is analyzed from the preparation of methanol-acetone recrystallization.Wherein, activated carbon and diatomaceous combination is used to carry out the decolorization process of benzazolyl compounds.
mp222.5-222.8℃。1HNMR(200MHz,DMSO-d6): δ 3.81 (s, 3H), 3.84 (s, 3H), 3.86 (s, 3H), 6.90 (d, 1H), 7.00 (d, J=1.2Hz, 1H), 7.09 (d, J=8.2Hz, 1H), 7.38 (s, 1H), 7.45 (d, J=8.2Hz, 1H), 7.88 (d, J=2.6Hz, 1H), 8.09 (d, J=8.8Hz, 1H), 11.8 (br, 1H, NH).13CNMR(50MHz,DMSO-d6):δ55.7,55.9,56.1,95.5,111.3,112.0,112.1,115.5,120.9,122.6,122.8,133.4,134.4,138.0,148.9,151.9,156.9,189.1。MS(EI)m/z312(MH+)。C18H17NO4Analytical calculation value: C69.44, H5.50, N4.50；Experiment value: C69.51, H5.54, N4.48.
Embodiment (seven)
The example 1 of the present invention
1-benzenesulfonyl-5-Methoxv-indole
At room temperature by Bu4NBr (330mg, 1.02mmol) and NaOH (630mg, 15.8mmol) adds 5-Methoxv-indole (1g, 6.8mmol) and is dissolved in dry CH2Cl2(60mL) solution, and stir the mixture for 30 minutes.Adding benzene sulfonyl chloride (1.2mL, 9.4mmol), reactant mixture at room temperature stirs 4 hours, reacts and terminates through add water (30mL).Organic layer is with saturated NaHCO3Aqueous solution (30mL) and water (30mLx2) washing, through Na2SO4Dry, and concentrating under reduced pressure.Residue produces 1-benzenesulfonyl-5-Methoxv-indole (1.18g, 60%) with silica gel column chromatography purification (purging with liquid: EtOAc/n-hexane1:9).
The example 2 of the present invention
1-benzenesulfonyl-5-methoxyl group-3-(3,4,5-trimethoxybenzoy) indole
At room temperature by AlCl3(660mg, 4.95mmol) adds 3,4,5-trimethoxy-benzoyl chloride (782mg, 3.39mmol) and is dissolved in dry CH2Cl2(20mL) solution, and stir the mixture for 20 minutes.Adding 1-benzenesulfonyl-5-Methoxv-indole (650mg, 2.26mmol), reactant mixture at room temperature stirs 2 hours, reacts and terminates through add water (30mL).Aqueous layer is with CH2Cl2(30mL) extract.The organic layer merged is with saturated NaHCO3Aqueous solution (30mLx2) and water (30mLx2) washing, through Na2SO4Dry, and concentrating under reduced pressure.Residue produces 1-benzenesulfonyl-5-methoxyl group-3-(3,4,5-trimethoxybenzoy) indole (320mg, 29%) with silica gel column chromatography purification (purging with liquid: EtOAc/n-hexane3:7).
The example 3 of the present invention
5-methoxyl group-3-(3,4,5-trimethoxybenzoy) indole
By K2CO3(220mg; 1.59mmol) add 1-benzenesulfonyl-5-methoxyl group-3-(3,4,5-trimethoxybenzoy) indole (300mg; 0.62mmol) in the suspension of methanol and aqueous mixtures, and reactant mixture is heated to reflux 1 hour.After methanol volatilization, add water 15mL.Solid collected by filtration is to obtain 5-methoxyl group-3-(3,4,5-trimethoxybenzoy) indole (173mg, 82%).Wherein, activated carbon and diatomaceous combination is used to carry out the decolorization process of benzazolyl compounds.
Above-described embodiment is used for illustrative purposes only, and is not limitation of the present invention, about the those of ordinary skill of technical field, without departing from the present invention, can also making a variety of changes and modification, therefore, all equivalent technical schemes also should belong to category disclosed by the invention.
Claims (24)
1. a synthetic method for benzazolyl compounds shown in Formulas I, including:
Starting indole shown in (i) Formula II and the first acylation reaction catalyst effect；
(ii) add chlorine acyl compounds shown in formula III, carry out acylation reaction with starting indole in organic solvent；
(iii) the second acylation reaction catalyst is added；
(iv) benzazolyl compounds is extracted；
Wherein said first acylation reaction catalyst is Grignard reagent and lewis acid；
Described second acylation reaction catalyst is lewis acid；
L1For chemical bond, C (O), O, S, NR, SO2Or CH2；
L2For chemical bond, C (O), O, S, NR, SO2Or CH2；
RlFor alkyl, ring base, heterocyclic radical, aryl or heteroaryl；
R2For H, alkyl, ring base, heterocyclic radical, aryl, heteroaryl, halogen, nitro, nitroso-group, cyano group, repeatedly nitrilo, different sulfur nitro, OR, OC (O) R, OC (O) OR, OC (O) NRR', SO2R、SO3R、SO2NRR'、SR、NRR'、NRSO2NR'R"、NRSO2R'、NRSO3R', NRC (O) R', NRC (O) NR'R ", NRC (O) OR', NRC (N) NR'R ", C (O) OR or C (O) NRR'；
Each Ra、Rb、RcWith RdRespectively R, halogen, nitro, nitroso-group, cyano group, repeatedly nitrilo, different sulfur nitro, OR, OC (O) R, OC (O) OR, OC (O) NRR', SO2R、SO3R、SO2NRR'、SR、NRR'、NRSO2NR'R"、NRSO2R'、NRSO3R', NRC (O) R', NRC (O) NR'R ", NRC (O) OR', NRC (N) NR'R ", C (O) R, C (O) OR or C (O) NRR' or RbWith Rc、RaWith Rb, or RcWith RdIt is O (CH together2)nO；And
ReFor H, alkyl, thiazolinyl, alkynyl, ring base, heterocyclic radical, aryl, heteroaryl, halogen, nitro, nitroso-group, cyano group, repeatedly nitrilo, different sulfur nitro, OR, OC (O) R, OC (O) OR, OC (O) NRR', SO2R、SO3R、SO2NRR'、SR、NRR'、NRSO2NR'R"、NRSO2R'、NRSO3R', NRC (O) R', NRC (O) NR'R ", NRC (O) OR', NRC (N) NR'R ", C (O) R, C (O) OR or C (O) NRR'；
Each of which R, R' and R " respectively H, alkyl, thiazolinyl, alkynyl, ring base, aryl, heteroaryl, ring base or heterocyclic radical, and n is 1,2,3,4 or 5；
Described acylation reaction carries out not higher than 25 DEG C when.
2. a synthetic method for benzazolyl compounds shown in Formulas I, including:
I () lewis acid reacts in organic solvent with chlorine acyl compounds shown in formula III；
(ii) add starting indole shown in Formula II to react；
(iii) benzazolyl compounds is extracted,
Wherein, L1、L2、Rl、R2、Ra、Rb、Rc、RdWith ReDefinition with according to claim 1 identical.
3. method according to claim 1 and 2, wherein L1For C (O), RlFor the alkyl replaced through alkoxyl, ring base, heterocyclic radical, aryl or heteroaryl.
4. method according to claim 3, wherein RlFor 3,4,5-2,4,5-trimethoxyphenyl.
5. method according to claim 1, wherein the first acylation reaction catalyst is ethylmagnesium bromide EtMgBr and zinc chloride ZnCl2。
6. method according to claim 1 and 2, wherein the second acylation reaction catalyst or lewis acid are zinc chloride ZnCl2, boron trifluoride BF3, aluminum chloride AlCl3, titanium tetrachloride TiCl4, ferric chloride FeCl3, butter of tin SnCl4, Columbium pentachloride. NbCl5Or the fluoroform sulphonate of lanthanide series.
7. method according to claim 1 and 2, wherein organic solvent is dichloromethane CH2Cl2, chloroform CHCl3, tetrachloromethane CCl4, vinyl chloride C2Cl4Or trichloro ethylene C2HCl3。
8., according to described method arbitrary in claim 1 and 3-7, described acylation reaction includes: ethylmagnesium bromide EtMgBr is added starting indole and zinc chloride ZnCl2With dichloromethane CH2Cl2Mixture in while, keep temperature not higher than 25 DEG C.
9. according to described method arbitrary in claim 1 and 3-7, wherein said acylation reaction farther includes: is added by chlorine acyl compounds while carrying out acylation reaction in mixture, keeps temperature not higher than 25 DEG C.
10., according to described method arbitrary in claim 1 and 3-7, wherein add the second acylation reaction catalyst and include: by aluminum chloride AlCl3While adding in mixture, keep temperature not higher than 25 DEG C.
11. according to described method arbitrary in claim 1 and 3-7, the time that wherein reacts was less than 5 hours.
12. according to described method arbitrary in claim 1 and 3-7, wherein, including: by ethylmagnesium bromide EtMgBr, starting indole and zinc chloride ZnCl2With dichloromethane CH2Cl2Mixed mixture is cooled to not higher than 25 DEG C.
13. according to described method arbitrary in claim 1-7; wherein, described acylation reaction carries out at the temperature of the group formed selected from temperature below condition: at 25 to-15 DEG C, 22.5 to-15 DEG C, 17.5 to-15 DEG C, at 15 to-15 DEG C, 12.5 to-12.5 DEG C, 10 to-10 DEG C, 7.5 to-7.5 DEG C, 5 to-5 DEG C, 2.5 to-2.5 DEG C, 25-15 DEG C, 15 to 12.5 DEG C, 12.5 to 10 DEG C, 10 to 7.5 DEG C, 7.5 to 5 DEG C, 5 to 2.5 DEG C, 2.5 to 0 DEG C, 0 to-2.5 DEG C ,-2.5 to-5 DEG C ,-5 to-10 DEG C ,-10 to-12.5 DEG C and-12.5 to-15 DEG C.
14. according to described method arbitrary in claim 1 or 2, wherein the concentration of chlorine acyl compounds is 0.5-4Mol/L；Or 0.5-2Mol/L；Or 0.5-1.5Mol/L；Or 0.5-1.2Mol/L.
15. the method according to claim 1 and 2 ,-L in starting indole shown in Formula II2-R2For blocking group, this blocking group is removed further after completion of the reaction.
16. method according to claim 13, wherein L2For SO2, R2For aryl.
17. method according to claim 1 and 2, the step of wherein said extraction benzazolyl compounds includes: change solvent or solvent exchange.
18. method according to claim 15, the step wherein changing solvent includes the organic layer after by extraction, is concentrated into dry and adds the second solvent；Wherein, benzazolyl compounds at the dissolubility of the second solvent lower than its dissolubility in the solvent of acylation reaction.
19. method according to claim 16, wherein dehydration adopts Na2S04, it includes Na2S04Join in the organic layer after extraction.
20. method according to claim 15; the step of wherein said solvent exchange includes the organic layer concentration after by extraction, adds the second solvent and heat the solvent to get rid of in acylation reaction and filter; wherein, benzazolyl compounds at the dissolubility of the second solvent lower than its dissolubility in the solvent of acylation reaction.
21. the method according to claim 16 or 18, wherein farther include: be heated to reflux after the solvent got rid of in acylation reaction, cooling, filter, and washing.
22. method according to claim 19, further the benzazolyl compounds extracted after described acylation reaction being purified, wherein purification step includes: dissolved in organic solvent by the thick product of benzazolyl compounds that acylation reaction is extracted；The mixture of benzazolyl compounds Yu organic solvent is heated to reflux；Control the temperature temperature range at the benzazolyl compounds intentionally got；It is cooled to mixture precipitate out critical state and filter；Wash and dry.
23. method according to claim 20, the thick product of benzazolyl compounds wherein extracted in acylation reaction adds activated carbon after dissolving in organic solvent；And after the mixture of benzazolyl compounds Yu organic solvent is heated to reflux, be filtered by kieselguhr.
null24. method according to claim 1 and 2，Wherein benzazolyl compounds shown in Formulas I selects free 6-methoxyl group-3-(3,4,5-trimethoxybenzoy) indole、6-methyl-3-(3,4,5-trimethoxybenzoy) indole、The fluoro-3-(3 of 6-,4,5-trimethoxybenzoy) indole、The bromo-3-(3 of 6-,4,5-trimethoxybenzoy) indole、4,5,6-trimethoxy-3-(3,4,5-trimethoxybenzoy) indole、5,6-dimethoxy-3-(3,4,5-trimethoxybenzoy) indole、6-methoxyl group-2-methyl-3-(3,4,5-trimethoxybenzoy) indole、6-ethyoxyl-3-(3,4,5-trimethoxybenzoy) indole、7-methoxyl group-3-(3,4,5-trimethoxybenzoy) indole、4-methoxyl group-3-(3,4,5-trimethoxybenzoy) indole、5-methoxyl group-4-methyl-3-(3,4,5-trimethoxybenzoy) indole、4,7-dimethoxy-3-(3,4,5-trimethoxybenzoy) indole、4,6-dimethoxy-3-(3,4,5-trimethoxybenzoy) indole、5,7-dimethoxy-3-(3,4,5-trimethoxybenzoy) indole、6-hydroxyl-3-(3,4,5-trimethoxybenzoy) indole、2-methyl-5-methoxyl group-3-(3,4,5-trimethoxybenzoy) indole、6-methoxyl group-3-(3,4-Dimethoxybenzoyl) indole and 5-methoxyl group-3-(3,4,5-trimethoxybenzoy) group of indole composition.
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| US11820747B2 (en) | 2021-11-02 | 2023-11-21 | Flare Therapeutics Inc. | PPARG inverse agonists and uses thereof |
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| US11944622B2 (en) | 2018-10-05 | 2024-04-02 | Annapurna Bio, Inc. | Compounds and compositions for treating conditions associated with APJ receptor activity |
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