CN103304466A - Synthetic method of 3-alkyl-substituted indole compound - Google Patents
Synthetic method of 3-alkyl-substituted indole compound Download PDFInfo
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- CN103304466A CN103304466A CN2013102209286A CN201310220928A CN103304466A CN 103304466 A CN103304466 A CN 103304466A CN 2013102209286 A CN2013102209286 A CN 2013102209286A CN 201310220928 A CN201310220928 A CN 201310220928A CN 103304466 A CN103304466 A CN 103304466A
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- AICKTEUXJKGWCK-UHFFFAOYSA-N Brc1ccc2[nH]cc(CCCc3ccccc3)c2c1 Chemical compound Brc1ccc2[nH]cc(CCCc3ccccc3)c2c1 AICKTEUXJKGWCK-UHFFFAOYSA-N 0.000 description 1
- MFCNTWPTEPRQDX-UHFFFAOYSA-N C(Cc1c[nH]c2c1cccc2)C1CNCCC1 Chemical compound C(Cc1c[nH]c2c1cccc2)C1CNCCC1 MFCNTWPTEPRQDX-UHFFFAOYSA-N 0.000 description 1
- XLVORGNTOFMQLB-UHFFFAOYSA-N CC(C)(CCc1c[nH]c2ccccc12)Cl Chemical compound CC(C)(CCc1c[nH]c2ccccc12)Cl XLVORGNTOFMQLB-UHFFFAOYSA-N 0.000 description 1
- BOAJOAAHUDSFRX-UHFFFAOYSA-N CCC1C(CCc2c[nH]c3ccccc23)CCNC1 Chemical compound CCC1C(CCc2c[nH]c3ccccc23)CCNC1 BOAJOAAHUDSFRX-UHFFFAOYSA-N 0.000 description 1
- MAXUZMXVDRZJQA-UHFFFAOYSA-N CCCNCCCc1c[nH]c2ccccc12 Chemical compound CCCNCCCc1c[nH]c2ccccc12 MAXUZMXVDRZJQA-UHFFFAOYSA-N 0.000 description 1
- CIGLRRQEHPLMAF-UHFFFAOYSA-N COc1ccc(c(CCCc(cc2)ccc2-c(cc2)ccc2Oc2ccc(c(CCN3CCNCC3)c[nH]3)c3c2)c[nH]2)c2c1 Chemical compound COc1ccc(c(CCCc(cc2)ccc2-c(cc2)ccc2Oc2ccc(c(CCN3CCNCC3)c[nH]3)c3c2)c[nH]2)c2c1 CIGLRRQEHPLMAF-UHFFFAOYSA-N 0.000 description 1
- DFWAZVNYWUGIFM-UHFFFAOYSA-N Cc1c(CCCl)c2ccccc2[nH]1 Chemical compound Cc1c(CCCl)c2ccccc2[nH]1 DFWAZVNYWUGIFM-UHFFFAOYSA-N 0.000 description 1
- JRASUUTVFCLPPO-UHFFFAOYSA-N ClCCc1c[nH]c2ccccc12 Chemical compound ClCCc1c[nH]c2ccccc12 JRASUUTVFCLPPO-UHFFFAOYSA-N 0.000 description 1
- WYICVZCBFLADDG-UHFFFAOYSA-N Fc1ccc2[nH]cc(CCCCN3CCNCC3)c2c1 Chemical compound Fc1ccc2[nH]cc(CCCCN3CCNCC3)c2c1 WYICVZCBFLADDG-UHFFFAOYSA-N 0.000 description 1
- YUNFFZXVNCXVCK-UHFFFAOYSA-N N#Cc1ccc2[nH]cc(CCN3CCNCC3)c2c1 Chemical compound N#Cc1ccc2[nH]cc(CCN3CCNCC3)c2c1 YUNFFZXVNCXVCK-UHFFFAOYSA-N 0.000 description 1
- GZQBGZWAALHNBW-UHFFFAOYSA-N NCCCCc1c[nH]c2c1cccc2 Chemical compound NCCCCc1c[nH]c2c1cccc2 GZQBGZWAALHNBW-UHFFFAOYSA-N 0.000 description 1
- IGLKHWVIJCQODS-UHFFFAOYSA-N OCCCCc1c[nH]c2ccccc12 Chemical compound OCCCCc1c[nH]c2ccccc12 IGLKHWVIJCQODS-UHFFFAOYSA-N 0.000 description 1
Classifications
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a synthetic method of a 3-alkyl-substituted indole compound. The synthetic method comprises the following steps of: (1) obtaining an product 1 by using the indole compound without a substituent group at 3-site as the starting material and using protective reagent to protect the nitrogen atom on the indole ring; (2) enabling the product 1 and acyl chloride to carry out a Friedel-Crafts acylation reaction to obtain the indole compound with a carbonyl group at the 3-stie; (3) enabling the product in the last step and sodium borohydride (or potassium borohydride)- trifluoroacetic acid to react, so that the indole 3-site carbonyl group is reduced into methylene, and the product 2 is obtained; and (4) removing protective group from the product 2 to obtain a target compound 3-alkyl-substituted indole.
Description
Technical field
The present invention relates to a kind of synthetic method of 3-alkyl substitution indole compounds, this compounds is important medicine intermediate.
Background technology
Benzazole compounds is the important intermediate of medicine, agricultural chemicals, other fine chemical product of dye well, and 3-alkyl substitution indole compounds wherein is important medicine intermediate especially.That the nervous tissues such as research and development cardiac-cerebral ischemia, arteriosclerosis, diabetes, rheumatic arthritis are degenerated and the key intermediate of ageing disorders new drug such as the 5-etryptamine:
And 3-(4-chlorobutyl)-5-cyanoindole is the key intermediate of synthetic depression new drug vilazodone.Vilazodone is by the development of Trovis Pharma LLC drugmaker, is used for the treatment of a kind of new drug of major depressive disorder, and the U.S. on the 21st food and medicine supervision and management January in 2011 (FDA) approval Vilazodone Hydrochloride sheet is used for the treatment of the middle major depressive disorder of growing up.
Study right personnel synthetic and studied many 3-alkyl substitution indole compounds, their major part is organic synthesis intermediate important in the new drug research, and the structural formula of some compounds is exemplified below:
Synthesizing of this compounds, the method for bibliographical information generally is take substituted indole as raw material, generates corresponding carbonyl compound through friedel-crafts acylation first, becomes methylene radical to get target product carbonyl reduction again, is shown below:
The method that reduction reaction is taked mainly contains following several: what (1) report was maximum is tetrahydrochysene lithium aluminum reduction method, such as document Bioorganic﹠amp; Medicinal Chemistry, 2009,17,6073-6084; Journal of Medcinal Chemistry, 2005,48,353-356; Tetrahedron, 1985,41 (6), the report such as 1039-1047; (2) method commonly used also has the borane reduction method, such as document Journal ofMedcinal Chemistry, 2010,53,8298-8308; Journal of Medcinal Chemistry, the report such as 2005,48,1781-1795; (3) sodium borohydride system, such as document Tetrahedron, 1995,51 (22), the sodium borohydride of 6255-6266 report-water reduction system and document Synthetic Communications, 1993,23 (8), the sodium borohydride-Virahol of 1101-1110 report-diglyme with; (4) document Journal of Organic Chemistry, 1992,57,3636-3642 and Tetrahedron Letters, 1990,31 (17), trifluoroacetyl oxygen sodium borohydride and the aluminum hydride reduction method of 2381-2384 report; (5) document Journal ofMedicinal Chemistry, 2004,47 (19), the red aluminium reducing method of 4684-4692 report.
The method of above-mentioned bibliographical information, its advantage are that reaction scheme is short, are convenient to make fast required target compound need for deliberation.But these methods also exist following shortcoming: reaction process poor stability, reaction can produce obvious by product, product purification is difficult, productive rate is low, only has 27% such as red aluminium reducing method product through productive rate behind the post.Be subjected to the restriction of these shortcomings, these synthetic methods are not suitable for amplifying.
Summary of the invention
The purpose of this invention is to provide a kind of safe, good reaction selectivity, product and be easy to purifying, with low cost, the synthetic method that is fit to the 3-alkyl substitution indole compounds that amplifies.Synthetic method provided by the present invention is shown below:
Wherein, R is the C1-C7 alkyl that C1-C7 alkyl or aryl that C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 aminoalkyl group, C1-C7 hydroxyalkyl, alcoxyl replace replaces, and the C1-C7 alkyl that the C1-C7 alkyl that described C1-C7 haloalkyl, C1-C7 aminoalkyl group, C1-C7 hydroxyalkyl, alcoxyl replace and aryl replace does not contain and easily is reduced or the substituted alkyl of nitro, ethylene linkage and the acetylene bond etc. of hydrogenation.
R
1Be the electron donating groups such as H, halogen atom, alkyl or substituted alkyl, substituted alkyl does not comprise the substituting group of groups such as containing amino, hydroxyl, sulfydryl, nitro, ethylene linkage, acetylene bond.
R
2, R
3, R
4And R
5Independent is the groups such as H, halogen atom, cyano group, alkyl, substituted alkyl and alkoxyl group, and substituted alkyl does not comprise nitro, amino, hydroxyl, sulfydryl, ethylene linkage, acetylene bond or contains the substituting group of these groups.
The synthetic method of 3-alkyl substitution indole compounds provided by the invention may further comprise the steps:
1) take the Benzazole compounds of 3-position unsubstituted as starting raw material, with nitrogen-atoms on the protection reagent protection indole ring, and product 1;
2) products therefrom 1 carries out friedel-crafts acylation reaction with acyl chlorides, gets the benzazolyl compounds of 3-position ketocarbonyl-containing;
3) step 2) product and sodium borohydride-trifluoroacetic acid or POTASSIUM BOROHYDRIDE-trifluoroacetic acid react, and indoles 3-position ketone carbonyl is reduced into methylene radical, and get product 2;
4) products therefrom 2 is sloughed protecting group and is got target compound 3-alkyl substitution indole under alkaline condition.
Described blocking group is a kind of in benzenesulfonyl (Bs), p-toluenesulfonyl (Ts), methylsulfonyl (Ms), tertbutyloxycarbonyl (Boc), carbobenzoxy-(Cbz) (CBz), ethanoyl (Ac), the trifluoroacetyl group (Tf).Accordingly, protection reagent then is a kind of in benzene sulfonyl chloride, Tosyl chloride, methylsulfonyl chloride, two dimethyl dicarbonate butyl methyl esters, chloroformic acid benzyl ester, Acetyl Chloride 98Min. (diacetyl oxide) and the trifluoroacetic anhydride.
Described acyl chlorides molecular formula is RCOCl, wherein R is the C1-C7 alkyl that C1-C7 alkyl or aryl that the alkyl, C1-C7 haloalkyl, C1-C7 aminoalkyl group, C1-C7 hydroxyalkyl, alcoxyl of C1-C7 replaces replaces, but does not comprise containing and easily be reduced or the substituted alkyl of the groups such as the nitro of hydrogenation, ethylene linkage, acetylene bond.R is preferably carbonatoms 1-5 in the acyl chlorides molecule, be that R is that C1-C5 alkyl, especially the R carbonatoms that C1-C5 alkyl or aryl that C1-C5 alkyl, C1-C5 haloalkyl, C1-C5 aminoalkyl group, C1-C5 hydroxyalkyl, alcoxyl replace replaces is alkane acyl chlorides or the haloalkane acyl chlorides of 1-5.
Described reductive agent system is comprised of a kind of and trifluoroacetic acid in sodium borohydride and the POTASSIUM BOROHYDRIDE, wherein the consumption of sodium borohydride or POTASSIUM BOROHYDRIDE be the substrate molar weight 2-20 doubly, be preferably 2-10 doubly, its adding mode is in batches adding; The consumption of trifluoroacetic acid be substrate molar weight 5-100 doubly, be preferably 10-30 doubly.
The solvent of described reduction reaction is a kind of in chloroform, acetonitrile, methylene dichloride and the ethylene dichloride.
The temperature of described reduction reaction is-10-10 ℃.
Described deprotection reaction is to carry out at alkaline condition.
Synthetic method provided by the invention, reduction reaction has avoided using the method that the danger coefficients such as tetrahydrochysene lithium aluminium, borine are high, reaction preference is poor, should not amplify, adopted gentle method of reducing, reaction can steadily be carried out smoothly, and reaction preference and productive rate are high.Advantage of the present invention is: reaction process is safe, the good reaction selectivity yield is high, product is easy to purifying, be fit to amplification.Additional benefit of the present invention is that its suitability is good, can be used to synthetic multiple this compounds, has larger practical value.
Embodiment
Below by specific embodiment technical scheme of the present invention is elaborated, cited embodiment is to describe in detail technical scheme of the present invention, and unrestricted protection scope of the present invention.
Synthesizing of embodiment 1:5-bromo-3-(3-chloro-3-methyl butyl) indoles
In the 5L there-necked flask, add 2L methylene dichloride and 196g5-bromo indole, after the stirring and dissolving, add the 120g sodium hydrate solid.The ice-water bath cooling keeps temperature to be lower than 20 ℃, adds the 200g p-methyl benzene sulfonic chloride in batches.Add after under room temperature stirring reaction spend the night.TLC monitoring raw material reaction is complete, and reaction solution is poured in the 1L frozen water, stirs 30 minutes.Separatory, water are used the 0.5L dichloromethane extraction again, merge organic phase, use successively dilute hydrochloric acid and water washing to neutral, and anhydrous sodium sulfate drying filters, and filtrate is directly used in throws next step.TLC＞95%, moisture content: 0.06%.
1L methylene dichloride and 400g aluminum chloride are joined in the 5L there-necked flask successively, and the ice-water bath cooling is lower, drips 232.5g3-chloro-3-Methylbutanoyl chloride, keeps temperature to be lower than 20 ℃ in the dropping process.After dripping off, insulated and stirred 1 hour.Then drip previous step gained methylene dichloride phase, keep temperature to be lower than 20 ℃ in the dropping process.Drip off, keep temperature＜10 a ℃ reaction to spend the night.The TLC monitoring reaction is complete, and reaction solution is poured in the frozen water, stir, and separatory, organic phase is washed till neutrality with saturated sodium bicarbonate solution, then washes with water.Organic phase is concentrated to be done, and adds the 1L hot ethanol and stirs 20 minutes, is chilled to room temperature, filters, drain, and alcohol flushing, drying obtains the 380g faint yellow solid, TLC＞95%, moisture content: 0.22%.Two-step reaction productive rate 81.1%.
Above-mentioned gained solid 380g, 4L methylene dichloride and 1.5kg trifluoroacetic acid are joined in the 10L reaction flask successively, stir.Cryosel is bathed-5 ℃ of coolings, adds the 160g sodium borohydride in batches, keeps temperature to be lower than 0 ℃.Add, spend the night in 0 ℃ of insulation reaction.The TLC demonstration reacts completely, and reaction solution is slowly poured in the frozen water, and constantly stirred, and keeps temperature to be lower than 20 ℃.Add, continue to stir 1 hour.Separatory, organic phase with saturated sodium bicarbonate solution and be washed to neutrality, then are concentrated into dried successively.Residuum adds the 1L hot ethanol, stirs 20 minutes, cools off, filters, drains, alcohol flushing, dry 333.4g white solid, HPLC＞97%, the productive rate 90.5% of getting.
Above-mentioned gained solid is joined in the 1.8L methyl alcohol, be heated to backflow, drip the aqueous solution (25%) that contains 35g sodium hydroxide.Drip off, continue reaction 30 minutes, the TLC monitoring adds frozen water to reacting completely under stirring, and stirs 1 hour.The solid filtering that produces, drain, use successively 1: 1 Methanol+Water and water flushing.Gained solid methylene dichloride recrystallization gets the 144g faint yellow solid and is product, HPLC＞98%, productive rate 65.3%.
1H?NMR(DMSO-d
6，400MHz)：δ11.04(s，1H，NH)，7.65(d，1H，H-4)，7.30(d，1H，H-7)，7.09-7.19(m，2H，H-2，6)，2.81(m，2H，CH
2)，2.13(m，2H，CH
2)，1.67(s，6H，CH
3)。
Synthesizing of embodiment 2:6-methoxyl group-3-(3-phenyl propyl) indoles
In the 5L there-necked flask, add 2L ethylene dichloride and 147g6-methoxy-Indole, after the stirring and dissolving, add the 95g sodium hydrate solid.The ice-water bath cooling keeps temperature to be lower than 25 ℃, adds the 213g benzene sulfonyl chloride in batches.Add after under room temperature stirring reaction spend the night.TLC monitoring raw material reaction is complete, and reaction solution is poured in the 1L frozen water, stirs 30 minutes.Separatory, water with the extraction of 0.5L ethylene dichloride, merge organic phase again, use successively dilute hydrochloric acid and water washing to neutral, and anhydrous sodium sulfate drying filters, and mother liquor is directly used in throws next step.TLC＞95%, moisture content: 0.17%.
1L ethylene dichloride and 350g Zinc Chloride Anhydrous are joined in the 5L there-necked flask successively, and the ice-water bath cooling is lower, drips 286g3-phenyl propionyl chloride, keeps temperature to be lower than 30 ℃ in the dropping process.After dripping off, insulated and stirred 1 hour.Then drip previous step gained dichloroethane solution, keep temperature to be lower than 25 ℃ in the dropping process.Drip off, keep temperature＜10 a ℃ reaction to spend the night.The TLC monitoring reaction is complete, and reaction solution is poured in the frozen water, stir, separatory, organic phase successively with saturated sodium bicarbonate solution be washed to neutrality.Organic phase is concentrated into dried, adds the 850mL hot methanol and stirs 30 minutes, is chilled to room temperature, filters, drains, the cold methanol flushing, and drying obtains the 362g faint yellow solid, TLC＞95%, moisture content: 0.35%.Two-step reaction productive rate 86.3%.
Above-mentioned gained all solids, 4L ethylene dichloride and 2.1kg trifluoroacetic acid are joined in the 10L reaction flask successively, stir.Cryosel is bathed-5 ℃ of coolings, adds the 216g POTASSIUM BOROHYDRIDE in batches, keeps temperature to be lower than 5 ℃.Add, spend the night in 5 ℃ of lower insulation reaction.The TLC demonstration reacts completely, and reaction solution is slowly poured in the frozen water, and constantly stirred, and keeps temperature to be lower than 15 ℃.Add, continue to stir 1 hour.Separatory, organic phase with saturated sodium bicarbonate solution and be washed to neutrality, then are concentrated into dried successively.Residuum adds the 1L hot methanol, stirs 20 minutes, cools off, filters, drains, cold methanol flushing, dry 299.6g off-white color solid, HPLC＞97%, the productive rate 85.6% of getting.
Above-mentioned gained solid is all joined 2L1: in 1 methanol-water, then add 150g salt of wormwood, be heated to and refluxed 2 hours.The TLC monitoring is cooled to room temperature to reacting completely, and adds frozen water, stirs 1 hour.The solid filtering that produces, drain, use successively 1: 1 Methanol+Water and water flushing.Gained solid ethylene dichloride recrystallization gets the 139g faint yellow solid and is product, HPLC＞98%, productive rate 70.9%.
1H?NMR(DMSO-d
6，400MHz)：δ11.15(s，1H，NH)，7.49(d，1H，H-4)，7.15(s，1H，H-2)，6.79-6.87(m，2H，H-5，7)，2.71(m，2H，CH
2)，2.60(m，2H，CH
2)，1.75(s，2H，CH
2)。
Synthesizing of embodiment 3:3-(4-chlorobutyl)-5-cyanoindole
In the 5L there-necked flask, add 2L ethylene dichloride and 147g5-cyanoindole, after the stirring and dissolving, add the 125g sodium hydrate solid.The ice-water bath cooling keeps temperature to be lower than 20 ℃, adds the 203g benzene sulfonyl chloride in batches.Add after under room temperature stirring reaction spend the night.TLC monitoring raw material reaction is complete, and reaction solution is poured in the 1L frozen water, stirs 30 minutes.Separatory, water with the extraction of 0.5L ethylene dichloride, merge organic phase again, use successively dilute hydrochloric acid and water washing to neutral, and anhydrous sodium sulfate drying filters, and mother liquor is directly used in throws next step.TLC＞95%, moisture content: 0.11%.
1L ethylene dichloride and 415g Zinc Chloride Anhydrous are joined in the 5L there-necked flask successively, and the ice-water bath cooling is lower, drips the 271g4-chlorobutanoylchloride, keeps temperature to be lower than 25 ℃ in the dropping process.After dripping off, insulated and stirred 1 hour.Then drip previous step gained dichloroethane solution, keep temperature to be lower than 25 ℃ in the dropping process.Drip off, keep temperature＜10 a ℃ reaction to spend the night.The TLC monitoring reaction is complete, and reaction solution is poured in the frozen water, stir, separatory, organic phase successively with saturated sodium bicarbonate solution be washed to neutrality.Organic phase is concentrated into dried, adds the 900mL hot methanol and stirs 30 minutes, is chilled to room temperature, filters, drains, the cold methanol flushing, and drying obtains the 325g faint yellow solid, TLC＞95%, moisture content: 0.22%.Two-step reaction productive rate 84.0%.
Above-mentioned gained all solids, 3.5L ethylene dichloride and 3.5kg trifluoroacetic acid are joined in the 10L reaction flask successively, stir.Cryosel is bathed-5 ℃ of coolings, adds the 386g POTASSIUM BOROHYDRIDE in batches, keeps temperature to be lower than 5 ℃.Add, spend the night in 5 ℃ of lower insulation reaction.The TLC demonstration reacts completely, and reaction solution is slowly poured in the frozen water, and constantly stirred, and keeps temperature to be lower than 20 ℃.Add, continue to stir 1 hour.Separatory, organic phase with saturated sodium bicarbonate solution and be washed to neutrality, then are concentrated into dried successively.Residuum adds the 1L hot methanol, stirs 20 minutes, cools off, filters, drains, cold methanol flushing, dry 279g white solid, HPLC＞97%, the productive rate 89.1% of getting.
1H?NMR(DMSO-d
6，400MHz)：δ8.22(d，1H，H-4)，8.09(d，1H，H-4)，7.88(d，2H)，7.81(s，1H，H-2)，7.74(dd，1H，H-6)，7.40(d，2H)，3.67(t，2H，CH
2)，2.71(t，2H，CH
2)，1.70-1.74(m，4H，CH
2CH
2)。
Above-mentioned gained solid is all joined 2L2: in 1 alcohol-water, then add 286g salt of wormwood, be heated to backflow.The TLC monitoring is cooled to room temperature to reacting completely, and adds frozen water, stirs 1 hour.The solid filtering that produces, drain, use successively 1: 1 ethanol-water mixed solvent and water flushing.The gained solid heats in the ethylene dichloride-water solvent that is dissolved in 2: 1, filtered while hot.Tell organic phase, solid is separated out in cooling, filters, dries to such an extent that the 117g faint yellow solid is product, HPLC＞98%, productive rate 67.3%.
1H?NMR(DMSO-d
6，400MHz)：δ11.39(s，1H，NH)，8.08(s，1H，H-2)，7.50(d，1H，H-7)，7.41(dd，1H，H-6)，7.35(d，1H，H-4)，3.68(t，2H，CH
2)，2.75(t，2H，CH
2)，1.75-1.79(m，4H，CH
2CH
2)。
Claims (8)
1. the synthetic method of a 3-alkyl substitution indole compounds may further comprise the steps:
Step 1: take the Benzazole compounds of 3-position unsubstituted as starting raw material, with nitrogen-atoms on the protection reagent protection indole ring, and product 1;
Step 2: products therefrom 1 carries out friedel-crafts acylation reaction with acyl chlorides, gets the benzazolyl compounds of 3-position ketocarbonyl-containing;
Step 3: with the benzazolyl compounds of step 2 3-position ketocarbonyl-containing and sodium borohydride-trifluoroacetic acid or POTASSIUM BOROHYDRIDE-trifluoroacetic acid reaction, make the 3-position ketone carbonyl on the benzazolyl compounds of described 3-position ketocarbonyl-containing be reduced into methylene radical, and product 2;
Step 4: products therefrom 2 is sloughed protecting group and is obtained 3-alkyl substitution indole shown in structural formula I:
Formula I
Wherein, R is the C1-C7 alkyl that C1-C7 alkyl or aryl that C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 aminoalkyl group, C1-C7 hydroxyalkyl, alcoxyl replace replaces, and the C1-C7 alkyl that the C1-C7 alkyl that described C1-C7 haloalkyl, C1-C7 aminoalkyl group, C1-C7 hydroxyalkyl, alcoxyl replace and aryl replace does not contain and easily is reduced or nitro, ethylene linkage and the acetylene bond of hydrogenation;
R
1Be H, halogen atom, alkyl or substituted alkyl;
R
2, R
3, R
4And R
5Independent is H, halogen atom, cyano group, alkyl, substituted alkyl or alkoxyl group;
Described substituted alkyl does not comprise and contains amino, hydroxyl, sulfydryl, nitro, ethylene linkage and acetylene bond.
2. the synthetic method of 3-alkyl substitution indole compounds according to claim 1, it is characterized in that described 3-position without the Benzazole compounds that replaces suc as formula shown in the II
R
1Be H, halogen atom, alkyl or substituted alkyl;
R
2, R
3, R
4And R
5Independent is H, halogen atom, cyano group, alkyl, substituted alkyl or alkoxyl group;
Described substituted alkyl does not comprise and contains amino, hydroxyl, sulfydryl, nitro, ethylene linkage and acetylene bond.
3. the synthetic method of 3-alkyl substitution indole compounds according to claim 1 is characterized in that described protection reagent is benzene sulfonyl chloride, Tosyl chloride, methylsulfonyl chloride, two dimethyl dicarbonate butyl methyl esters, chloroformic acid benzyl ester, Acetyl Chloride 98Min., diacetyl oxide or trifluoroacetic anhydride.
4. the synthetic method of 3-alkyl substitution indole compounds according to claim 1, it is characterized in that described R is the C1-C5 alkyl that C1-C5 alkyl or aryl that C1-C5 alkyl, C1-C5 haloalkyl, C1-C5 aminoalkyl group, C1-C5 hydroxyalkyl, alcoxyl replace replaces, the C1-C5 alkyl that the C1-C5 alkyl that described C1-C5 haloalkyl, C1-C5 aminoalkyl group, C1-C5 hydroxyalkyl, alcoxyl replace and aryl replace does not contain and easily is reduced or nitro, ethylene linkage and the acetylene bond of hydrogenation.
5. the synthetic method of 3-alkyl substitution indole compounds according to claim 1, it is characterized in that described sodium borohydride-trifluoroacetic acid or POTASSIUM BOROHYDRIDE-trifluoroacetic acid, wherein the consumption of sodium borohydride or POTASSIUM BOROHYDRIDE be the substrate molar weight 2-20 doubly, its adding mode is in batches adding; The consumption of trifluoroacetic acid be substrate molar weight 5-100 doubly.
6. the synthetic method of 3-alkyl substitution indole compounds according to claim 1 is characterized in that solvent for use in the described step 3 is a kind of in chloroform, acetonitrile, methylene dichloride and the ethylene dichloride.
7. the synthetic method of 3-alkyl substitution indole compounds according to claim 1 is characterized in that the temperature of reaction of described step 3 is-10 ℃-10 ℃.
8. the synthetic method of 3-alkyl substitution indole compounds according to claim 1 is characterized in that described step 4 deprotection reaction is to carry out at alkaline condition.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103709089A (en) * | 2013-12-31 | 2014-04-09 | 南通恒盛精细化工有限公司 | Method for preparing 3-(4'-chlorobutyl)-5-cyanoindole |
| US9533949B2 (en) | 2012-09-12 | 2017-01-03 | Apotex Pharmachem Inc. | Processes for the preparation of 3-alkyl indoles |
| CN109928867A (en) * | 2017-12-15 | 2019-06-25 | 江苏暨明医药科技有限公司 | The synthetic method of penta benzene of 3,5- dihydroxy |
| CN110372746A (en) * | 2019-07-11 | 2019-10-25 | 辽宁石油化工大学 | A method of synthesis beta-amido phosphine oxide compound |
| CN111087340A (en) * | 2019-11-29 | 2020-05-01 | 上海应用技术大学 | Preparation method of vilazodone intermediate |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000035872A1 (en) * | 1998-12-17 | 2000-06-22 | Merck Patent Gmbh | Method for producing 3-alkanoylindoles and 3-alkylindoles |
| US6358992B1 (en) * | 1998-11-25 | 2002-03-19 | Cell Pathways, Inc. | Method of inhibiting neoplastic cells with indole derivatives |
| WO2008006790A1 (en) * | 2006-07-14 | 2008-01-17 | Glaxo Group Limited | Indole compounds |
| WO2008006793A1 (en) * | 2006-07-14 | 2008-01-17 | Glaxo Group Limited | Indole compounds |
| CN102617558A (en) * | 2012-03-26 | 2012-08-01 | 上海泛凯生物医药科技有限公司 | Preparation method of vilazodone |
| CN102659660A (en) * | 2012-05-11 | 2012-09-12 | 杭州和泽医药科技有限公司 | Preparation method and application of 3-(4-chlorobutyl)-5-cyano-1H-indole |
| CN102690224A (en) * | 2012-04-16 | 2012-09-26 | 淮海工学院 | Preparation method for 3-(4- chlorobutyl)-1H-5-cyanoindole as a vilazodone intermediate |
| CN103058912A (en) * | 2012-12-28 | 2013-04-24 | 山东邹平大展新材料有限公司 | Preparation method of 3-(4-chlorobutyl)indole-5-formonitrile |
-
2013
- 2013-05-18 CN CN2013102209286A patent/CN103304466A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6358992B1 (en) * | 1998-11-25 | 2002-03-19 | Cell Pathways, Inc. | Method of inhibiting neoplastic cells with indole derivatives |
| WO2000035872A1 (en) * | 1998-12-17 | 2000-06-22 | Merck Patent Gmbh | Method for producing 3-alkanoylindoles and 3-alkylindoles |
| WO2008006790A1 (en) * | 2006-07-14 | 2008-01-17 | Glaxo Group Limited | Indole compounds |
| WO2008006793A1 (en) * | 2006-07-14 | 2008-01-17 | Glaxo Group Limited | Indole compounds |
| CN102617558A (en) * | 2012-03-26 | 2012-08-01 | 上海泛凯生物医药科技有限公司 | Preparation method of vilazodone |
| CN102690224A (en) * | 2012-04-16 | 2012-09-26 | 淮海工学院 | Preparation method for 3-(4- chlorobutyl)-1H-5-cyanoindole as a vilazodone intermediate |
| CN102659660A (en) * | 2012-05-11 | 2012-09-12 | 杭州和泽医药科技有限公司 | Preparation method and application of 3-(4-chlorobutyl)-5-cyano-1H-indole |
| CN103058912A (en) * | 2012-12-28 | 2013-04-24 | 山东邹平大展新材料有限公司 | Preparation method of 3-(4-chlorobutyl)indole-5-formonitrile |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9533949B2 (en) | 2012-09-12 | 2017-01-03 | Apotex Pharmachem Inc. | Processes for the preparation of 3-alkyl indoles |
| CN103709089A (en) * | 2013-12-31 | 2014-04-09 | 南通恒盛精细化工有限公司 | Method for preparing 3-(4'-chlorobutyl)-5-cyanoindole |
| CN103709089B (en) * | 2013-12-31 | 2015-08-19 | 南通恒盛精细化工有限公司 | One prepares the method for 3-(4 '-chlorobutyl)-5-cyanoindole |
| CN109928867A (en) * | 2017-12-15 | 2019-06-25 | 江苏暨明医药科技有限公司 | The synthetic method of penta benzene of 3,5- dihydroxy |
| CN109928867B (en) * | 2017-12-15 | 2022-04-12 | 江苏暨明医药科技有限公司 | Method for synthesizing 3, 5-dihydroxyl pentylbenzene |
| CN110372746A (en) * | 2019-07-11 | 2019-10-25 | 辽宁石油化工大学 | A method of synthesis beta-amido phosphine oxide compound |
| CN111087340A (en) * | 2019-11-29 | 2020-05-01 | 上海应用技术大学 | Preparation method of vilazodone intermediate |
| CN111087340B (en) * | 2019-11-29 | 2021-12-07 | 上海应用技术大学 | Preparation method of vilazodone intermediate |
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