CN104098499B - The preparation method of 5-benzyloxy-2-(4-benzyloxy phenyl)-3-Methyl-1H-indole - Google Patents

The preparation method of 5-benzyloxy-2-(4-benzyloxy phenyl)-3-Methyl-1H-indole Download PDF

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CN104098499B
CN104098499B CN201310120074.4A CN201310120074A CN104098499B CN 104098499 B CN104098499 B CN 104098499B CN 201310120074 A CN201310120074 A CN 201310120074A CN 104098499 B CN104098499 B CN 104098499B
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acid
preparation
reaction
benzyloxy
compound
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CN104098499A (en
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陈姗
袁哲东
刘相奎
孔锐
顾红梅
王祥建
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Shanghai Institute of Pharmaceutical Industry
Chia Tai Tianqing Pharmaceutical Group Co Ltd
China State Institute of Pharmaceutical Industry
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Shanghai Institute of Pharmaceutical Industry
Chia Tai Tianqing Pharmaceutical Group Co Ltd
China State Institute of Pharmaceutical Industry
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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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  • Organic Chemistry (AREA)
  • Indole Compounds (AREA)

Abstract

The invention discloses the preparation method of 5-benzyloxy-2-(4-benzyloxy phenyl)-3-Methyl-1H-indole. This preparation method comprises the following steps: that (1) is in alcohols solvent, under the effect of alkali, Compound I I and compound III is carried out to condensation reaction; (2) reactant liquor of step (1) is mixed with Bronsted acid, carries out Bischler-Mohlau indoles ring closure reaction. Synthetic route of the present invention is compared with original technology, first step condensation reaction is merged into " one pot " with second step Bischler-Mohlau indoles ring closure reaction and react, easy and simple to handle; Product I directly separates out from reaction dissolvent, has greatly simplified post-reaction treatment process, and purity is high, and reaction yield is high, is suitable for amplifying producing.

Description

The preparation method of 5-benzyloxy-2-(4-benzyloxy phenyl)-3-Methyl-1H-indole
Technical field
The present invention relates to the preparation method of 5-benzyloxy-2-(4-benzyloxy phenyl)-3-Methyl-1H-indole.
Background technology
The WAY 140424 (bazedoxifene) of being developed by Wyeth company is that SERM(of new generation is selectively femaleHormone receptor conditioning agent), it can suppress the combination of 17 beta estradiols and ER α and ER β competitively,Using is separately without agonist activity to human breast cancer cell. Preclinical test demonstration, in like product,It is improving aspect the characteristic of uterus than Raloxifene (second generation SERM) and the lasofoxifene (third generationSERM) have more advantage, in addition, the demonstration of vasomotor instability model test, it is to central nervous systemSystem side effect is very little, aspect activation hepatic lipase promoter, and the activator that it is a kind of relative efficiency, andRaloxifene is invalid, and when with Raloxifene coupling, it can suppress Raloxifene to rodentThe spread effect in uterus, the two is different to the effect in uterus as seen. Preclinical test data show,It has more target activity than other SERMs known today, is " the best in like product " so far.This medicine at present in 2009 European Union's (trade name: Conbriza) and Japan (trade name: Viviant)Listing. Its primary indication is the osteoporosis for the treatment of and prevention menopausal women.
Bazedoxifene acetate (Bazedoxifeneacetate) chemistry 1-{4-[2-(cycloheximide base-1-) by nameEthyoxyl] benzyl }-2-(4-hydroxy phenyl)-3-Methyl-1H-indole-5-phenol acetate, its preparation method is as follows:
5-benzyloxy-2-(4-benzyloxy phenyl)-3-Methyl-1H-indole (I) is acetic acid synthesized WAY 140424Key intermediate, it synthesizes the following three kinds of methods that mainly contain:
Route one (US5998402):
This route taking 2-bromo-(4-benzyloxy phenyl) acetone (II), to benzyloxy aniline hydrochloride (III) asInitiation material, taking DMF as solvent, back flow reaction, II and III condensation obtain 5-benzyloxy-2-(4-benzyloxyBase phenyl)-3-Methyl-1H-indole (I). In this reaction, to the use of benzyloxy aniline hydrochloride (III)Amount is 3.5 times (mole ratios) of 2-bromo-(4-benzyloxy phenyl) acetone (II), has a large amount of to benzyloxyBase anilinechloride (III) residue, had both brought trouble to post processing, needed column chromatography purification, again waveTake raw material, and yield low (33%), be not suitable for suitability for industrialized production.
Route two (US5998402):
This route taking route one as basis, equally with 2-bromo-(4-benzyloxy phenyl) acetone (II), to benzyloxyBase anilinechloride (III) is initiation material, and taking DMF as solvent, II and III condensation obtain 5-benzyloxyBase-2-(4-benzyloxy phenyl)-3-Methyl-1H-indole (I). Different, in this route, two-step reaction closesAnd be " one pot " reaction: in the first step, add triethylamine to make alkali, the III condensation of II and 1.3 times of molesObtain intermediate product 1-(4-benzyloxy phenyl)-2-[(4-benzyloxy phenyl) amino] acetone (IV), IV is without dividingFrom, there is the life of Bischler-Mohlau indoles ring closure reaction with the III of 1.5 times of moles that again addBecome product I. Although this route is merged into two-step reaction " one pot ", has simplified operation, forRemove excessive III and impurity, post-processing step is loaded down with trivial details, and gained solid crude product need be many in methanol/etherInferior making beating washing just can obtain purer product I, yield lower (55%).
Route three (WO2008098527):
This route taking 2-bromo-(4-benzyloxy phenyl) acetone (II), to benzyloxy aniline hydrochloride (III) asInitiation material (is 2-bromo-(4-benzyloxy phenyl) acetone (II) to the consumption of benzyloxy aniline hydrochloride (III)1.1-1.2 doubly), make solvent with alcohol (ethanol, isopropyl alcohol etc.), condensation obtains intermediate 1-(4-benzyloxyPhenyl)-2-[(4-benzyloxy phenyl) amino] acetone (IV), by after IV separation and purification, IV again with 0.2 timesThere is Bischler-Mohlau indoles ring closure reaction and obtain product I in the III of mole. This route yield is higher(two step total recovery 60%-75%), but intermediate product IV needs separation and purification, has increased operation,Whole piece route is succinct not.
Summary of the invention
Technical problem solved by the invention is in order to overcome existing 5-benzyloxy-2-(4-benzyloxy benzeneBase) the defect such as-complicated process of preparation of 3-Methyl-1H-indole, complex operation, productive rate be low, provide onePlant the preparation method of 5-benzyloxy-2-(4-benzyloxy phenyl)-3-Methyl-1H-indole. This preparation method's operationSimply, cost is low, has greatly simplified post-reaction treatment process, and purity is high, and reaction yield is high, is suitable forAmplify and produce.
The present invention solves the problems of the technologies described above by the following technical programs:
The invention provides the preparation method of 5-benzyloxy-2-(4-benzyloxy phenyl)-3-Methyl-1H-indole,It comprises the following steps:
(1), in alcohols solvent, under the effect of alkali, Compound I I and compound III are carried out to condensationReaction;
(2) reactant liquor of step (1) is mixed with Bronsted acid, carry out Bischler-Mohlau indoles passRing reaction;
In step (1), described alcohols solvent is preferably n-butanol, isobutanol, normal propyl alcohol, differentOne or more in propyl alcohol and ethanol; Be more preferably a kind of in n-butanol, isobutanol and normal propyl alcohol orMultiple. Described alcohols solvent is 5～15ml/g with the volume mass of Compound I I than preferably.
In step (1), described alkali is preferably inorganic base and/or organic base. Described inorganic baseBe one in potash, sodium carbonate, sodium acid carbonate, saleratus, NaOH and potassium hydroxide goodlyKind or multiple; Described organic base is preferably triethylamine, pyridine, 4-dimethylaminopyridine, morpholineWith one or more in DIPEA. Described alkali is more preferably triethylamine. Described alkaliWith the mol ratio of Compound I I be preferably (2:1)～(2.5:1).
In step (1), described Compound I I and the mol ratio of compound III be preferably (1:1)～（1:1.2）。
In step (1), the temperature of described condensation reaction is preferably 75～160 DEG C, is more preferably100～130 DEG C. The process of described condensation reaction can pass through this area conventional means (as TLC orHPLC) monitor, while generally disappearance using Compound I I, as the terminal of reaction, described condensation is anti-The time of answering is preferably 2～4 hours.
In the present invention, the reactant liquor that described step (1) obtains can directly carry out step without post processing （2）。
In step (2), before the reactant liquor of step (1) is mixed with Bronsted acid, preferably carry out coldBut. Described cooling preferably for the temperature of the reactant liquor that naturally cools to described step (1) is10～30℃。
In step (2), described Bronsted acid is preferably inorganic acid and/or organic acid. Described is inorganicAcid is preferably one or more in hydrochloric acid, sulfuric acid and phosphoric acid, is more preferably hydrochloric acid; Described is organicAcid be preferably formic acid, acetic acid, propionic acid, oxalic acid, fumaric acid, maleic acid, butanedioic acid, tartaric acid,In citric acid, malonic acid, methanesulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid and p-methyl benzenesulfonic acid monohydrateOne or more are more preferably p-methyl benzenesulfonic acid. The mol ratio of described Bronsted acid and Compound I I is betterGround is (0.05:1)～(0.3:1).
In step (2), the temperature of described Bischler-Mohlau indoles ring closure reaction is preferably75～160 DEG C, be more preferably 100～130 DEG C.
The process of described Bischler-Mohlau indoles ring closure reaction can pass through this area conventional means (asTLC or HPLC) to monitor, the time of described Bischler-Mohlau indoles ring closure reaction is betterGround is 5～15 hours.
Wherein, after finishing, described Bischler-Mohlau indoles ring closure reaction can also carry out post processing,Be further purified Compound I. The mode of described post processing can be the post processing mode of this area routine,Preferably include following steps: suction filtration, dry. In the time that described alkali adopts inorganic base, after suction filtrationPreferably wash, drier.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can be combined, and obtains thisInvent each preferred embodiments.
Agents useful for same of the present invention and raw material be commercially available obtaining all.
Positive progressive effect of the present invention is: synthetic route of the present invention is compared with original technology, willFirst step condensation reaction is merged into " one pot " with second step Bischler-Mohlau indoles ring closure reaction and is reacted,Easy and simple to handle; In reactant liquor, add acid, without again adding starting compound III, simplified operation, jointEconomize cost; Product I directly separates out from reaction dissolvent, has greatly simplified post-reaction treatment process,And purity is high, reaction yield is high, is suitable for amplifying producing.
Detailed description of the invention
Mode below by embodiment further illustrates the present invention, but does not therefore limit the present invention toAmong described scope of embodiments. The experimental technique of unreceipted actual conditions in the following example, according to oftenRule method and condition, or select according to catalogue.
Embodiment 1
Synthetic 5-benzyloxy-2-(4-benzyloxy phenyl)-3-Methyl-1H-indole (I)
2-bromo-(4-benzyloxy phenyl) acetone (12.7g, 0.04mol), to benzyloxy aniline hydrochloride (11.1g,0.047mol) add in n-butanol (120ml), add triethylamine (12.2ml), be warming up to 118 DEG CReflux, after 3 hours, 2-bromo-(4-benzyloxy phenyl) acetone reacts completely; Add concentrated hydrochloric acid (1.0ml),Be warming up to 118 DEG C and continue reaction 7 hours. Reactant liquor is cooling, and suction filtration is dried to obtain white solid 15.2g,HPLC purity: 98%, yield 90.5%.
1H-NMR(400MHz,d6-DMSO)δ(ppm):7.798(brs,1H,-NH-),7.102-7.557(m,14H,Ar-H),7.255(d,1H,J=2.4Hz,Ar-H),7.174(d,1H,J=4.0Hz,Ar-H),6.978(dd,1H,J=4.0Hz,2.4Hz,Ar-H),5.192(s,2H,-OCH2-),5.153(s,2H,-OCH2-),2.436(s,3H,-CH3)MS(m/z):420（M+1）
Embodiment 2
Synthetic 5-benzyloxy-2-(4-benzyloxy phenyl)-3-Methyl-1H-indole (I)
2-bromo-(4-benzyloxy phenyl) acetone (12.7g, 0.04mol), to benzyloxy aniline hydrochloride (11.1g,0.047mol) add in isobutanol (120ml), add triethylamine (12.2ml), be warming up to 107 DEG CReflux, after 3 hours, 2-bromo-(4-benzyloxy phenyl) acetone reacts completely; Add p-methyl benzenesulfonic acid one waterCompound (1.7g), is warming up to 107 DEG C and continues reaction 14 hours. Reactant liquor is cooling, suction filtration, drySepia solid 14.4g, HPLC purity: 97%, yield 86%.
Embodiment 3
Synthetic 5-benzyloxy-2-(4-benzyloxy phenyl)-3-Methyl-1H-indole (I)
2-bromo-(4-benzyloxy phenyl) acetone (12.7g, 0.04mol), to benzyloxy aniline hydrochloride (11.1g,0.047mol) add in isopropyl alcohol (120ml), add pyridine (7.1ml), be warming up to 84 DEG C, 4After hour, 2-bromo-(4-benzyloxy phenyl) acetone reacts completely; Add acetic acid (0.7ml) to continue reaction15 hours. Reactant liquor is cooling, and suction filtration is dried to obtain white solid 14.6g, HPLC purity: 96%,Yield 87%.
Embodiment 4
Synthetic 5-benzyloxy-2-(4-benzyloxy phenyl)-3-Methyl-1H-indole (I)
2-bromo-(4-benzyloxy phenyl) acetone (12.7g, 0.04mol), to benzyloxy aniline hydrochloride (11.1g,0.047mol) add in n-butanol (120ml), add morpholine (7.7ml), be warming up to 118 DEG C, 3After hour, 2-bromo-(4-benzyloxy phenyl) acetone reacts completely; Add the concentrated sulfuric acid (0.6ml), continue anti-Answer 7 hours. Reactant liquor is cooling, and suction filtration is dried to obtain white solid 14.7g, HPLC purity: 98%,Yield 88%.
Embodiment 5
Synthetic 5-benzyloxy-2-(4-benzyloxy phenyl)-3-Methyl-1H-indole (I)
2-bromo-(4-benzyloxy phenyl) acetone (12.7g, 0.04mol), to benzyloxy aniline hydrochloride (11.1g,0.047mol) add in n-butanol (120ml), add sodium carbonate (9.3g), be warming up to 118 DEG C and returnStream, after 3 hours, 2-bromo-(4-benzyloxy phenyl) acetone reacts completely; Add concentrated hydrochloric acid (1.0ml),Be warming up to 118 DEG C and continue reaction 7 hours. Reactant liquor is cooling, suction filtration, and gained solid washing (60ml),Filter, be dried to obtain white solid 14.8g, HPLC purity: 99%, yield 88%.

Claims (10)

  1. The preparation method of 1.5-benzyloxy-2-(4-benzyloxy phenyl)-3-Methyl-1H-indole, is characterized in that,It comprises the following steps:
    (1), in alcohols solvent, under the effect of alkali, Compound I I and compound III are carried out to condensationReaction;
    (2) reactant liquor of step (1) is mixed with Bronsted acid, carry out Bischler-Mohlau indoles passRing reaction;
  2. 2. preparation method as claimed in claim 1, is characterized in that, in step (1), describedAlcohols solvent is one or more in n-butanol, isobutanol, normal propyl alcohol, isopropyl alcohol and ethanol; DescribedAlcohols solvent be 5～15ml/g with the volume mass ratio of Compound I I.
  3. 3. preparation method as claimed in claim 1, is characterized in that, in step (1), describedAlkali is inorganic base and/or organic base, and described inorganic base is potash, sodium carbonate, sodium acid carbonate, carbonic acidOne or more in hydrogen potassium, NaOH and potassium hydroxide, described organic base be triethylamine, pyridine,One or more in 4-dimethylaminopyridine, morpholine and DIPEA.
  4. 4. preparation method as claimed in claim 1, is characterized in that, described alkali and Compound I IMol ratio be (2:1)～(2.5:1).
  5. 5. preparation method as claimed in claim 1, is characterized in that, in step (1), describedThe mol ratio of Compound I I and compound III is (1:1)～(1:1.2).
  6. 6. preparation method as claimed in claim 1, is characterized in that, in step (1), describedThe temperature of condensation reaction is 75～160 DEG C; In step (2), described Bischler-Mohlau indoles closesThe temperature of ring reaction is 75～160 DEG C.
  7. 7. preparation method as claimed in claim 6, is characterized in that, in step (1), describedThe temperature of condensation reaction is 100～130 DEG C; In step (2), described Bischler-Mohlau indolesThe temperature of ring closure reaction is 100～130 DEG C.
  8. 8. preparation method as claimed in claim 1, is characterized in that, in step (2), will walkSuddenly the reactant liquor of (1) carries out before mixing with Bronsted acid coolingly, and described being cooled to naturally cools to instituteThe temperature of the reactant liquor of the step (1) of stating is 10～30 DEG C.
  9. 9. preparation method as claimed in claim 1, is characterized in that, in step (2), describedBronsted acid is inorganic acid and/or organic acid; Described inorganic acid be a kind of in hydrochloric acid, sulfuric acid and phosphoric acid orMultiple; Described organic acid be formic acid, acetic acid, propionic acid, oxalic acid, fumaric acid, maleic acid, butanedioic acid,Tartaric acid, citric acid, malonic acid, methanesulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid and p-methyl benzenesulfonic acid one waterOne or more in compound.
  10. 10. preparation method as claimed in claim 1, is characterized in that, described Bronsted acid and chemical combinationThe mol ratio of thing II is (0.05:1)～(0.3:1).
CN201310120074.4A 2013-04-08 2013-04-08 The preparation method of 5-benzyloxy-2-(4-benzyloxy phenyl)-3-Methyl-1H-indole Active CN104098499B (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT201800006562A1 (en) * 2018-06-21 2019-12-21 PROCEDURE AND USEFUL INTERMEDIATES FOR THE PREPARATION OF INDOLES

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5880137A (en) * 1996-04-19 1999-03-09 American Home Products Corporation 2-phenyl-1- 4-(amino-1-yl-alk-1-ynyl)-benzyl!-1H-indol-5-ols as estrogenic agents
CN1309637A (en) * 1998-05-15 2001-08-22 美国家用产品公司 Compositions comprising 2-phenyl-indole compounds and estrogen formutations
WO2004099139A1 (en) * 2000-09-15 2004-11-18 Baylor University Indole-containing compounds with anti-tubulin and vascular targeting activity
WO2008098527A1 (en) * 2007-02-12 2008-08-21 Zentiva A.S. Method for the preparation of 5-benzyloxy-2-(4-benzyloxphenyl)-3-methyl-1h-indole

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2383988A1 (en) * 1999-09-17 2001-03-22 Baylor University Indole-containing and combretastatin-related anti-mitotic and anti-tubulin polymerization agents

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5880137A (en) * 1996-04-19 1999-03-09 American Home Products Corporation 2-phenyl-1- 4-(amino-1-yl-alk-1-ynyl)-benzyl!-1H-indol-5-ols as estrogenic agents
CN1309637A (en) * 1998-05-15 2001-08-22 美国家用产品公司 Compositions comprising 2-phenyl-indole compounds and estrogen formutations
WO2004099139A1 (en) * 2000-09-15 2004-11-18 Baylor University Indole-containing compounds with anti-tubulin and vascular targeting activity
WO2008098527A1 (en) * 2007-02-12 2008-08-21 Zentiva A.S. Method for the preparation of 5-benzyloxy-2-(4-benzyloxphenyl)-3-methyl-1h-indole

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
cient one-pot synthesis of indoles.《Tetrahedron Letters》.2007,第49卷全文. *
Design, Synthesis, and Preclinical Characterization of Novel, Highly Selective Indole Estrogens;Chris P.Miller等;《J.Med.Chem.》;20010425;第44卷(第11期);第1654-1657页 *
George Bratulescu.A new and e&#64259 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT201800006562A1 (en) * 2018-06-21 2019-12-21 PROCEDURE AND USEFUL INTERMEDIATES FOR THE PREPARATION OF INDOLES

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