CN104098499A - Preparation method for 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole - Google Patents

Preparation method for 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole Download PDF

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CN104098499A
CN104098499A CN201310120074.4A CN201310120074A CN104098499A CN 104098499 A CN104098499 A CN 104098499A CN 201310120074 A CN201310120074 A CN 201310120074A CN 104098499 A CN104098499 A CN 104098499A
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acid
preparation
reaction
benzyloxy
compound
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CN104098499B (en
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陈姗
袁哲东
刘相奎
孔锐
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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
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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Indole Compounds (AREA)

Abstract

The invention discloses a preparation method for 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole as shown in the specification. The preparation method comprises the following steps: (1) subjecting a compound II and a compound III to a condensation reaction in an alcohol solvent under the action of alkali; and (2) mixing a reaction solution obtained in the step (1) with protonic acid and carrying out Bischler-Mohlau indole cyclization. Compared with the prior art, the invention has the following advantages: the condensation reaction in the first step and Bischler-Mohlau indole cyclization at the second step are integrated into a one-pot reaction, so operation is simple and convenient; a reaction product I is directly precipitated from the reaction solvent, so reaction post-treatment is substantially simplified, and high purity and high reaction yield are realized; and the method is applicable to enlarged production.

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 SERM(selective estrogen receptor modulators of new generation), it can suppress the combination of 17 beta estradiols and ER α and ER β competitively, and using is separately without agonist activity to human breast cancer cell.Preclinical test shows, in like product, it has more advantage than raloxifene (s-generation SERM) and Lasofoxifene (third generation SERM) improving aspect the characteristic of uterus, in addition, vasomotor instability model trial shows, it is very little to central nervous system side effect, aspect activation hepatic lipase promoter, it is a kind of agonist of relative efficiency, raloxifene is invalid, when with raloxifene coupling, it can suppress the hormesis of raloxifene to rodent uterus, and 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, are " the bests in like product " so far.This medicine went on the market in European Union's (trade(brand)name: Conbriza) and Japan's (trade(brand)name: Viviant) in 2009 at present.Its primary indication is the osteoporosis for the treatment of and prevention menopausal women.
Bazedoxifene acetate (Bazedoxifene acetate) chemistry 1-{4-[2-(U-4527 base-1-) oxyethyl group by name] 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 the key intermediate of acetic acid synthesized WAY 140424, and 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) as starting raw material, taking DMF as solvent, back flow reaction, II and III condensation obtain 5-benzyloxy-2-(4-benzyloxy phenyl)-3-Methyl-1H-indole (I).In this reaction, to the consumption of benzyloxy aniline hydrochloride (III) be 3.5 times (molar weight ratios) of 2-bromo-(4-benzyloxy phenyl) acetone (II), there is a large amount of benzyloxy aniline hydrochloride (III) is remained, both brought trouble to aftertreatment, need column chromatography purification, waste again raw material, and yield low (33%), be not suitable for suitability for industrialized production.
Route two (US5998402):
This route is taking route one as basis, equally taking 2-bromo-(4-benzyloxy phenyl) acetone (II), to benzyloxy aniline hydrochloride (III) as starting raw material, taking DMF as solvent, II and III condensation obtain 5-benzyloxy-2-(4-benzyloxy phenyl)-3-Methyl-1H-indole (I).Different is, in this route, two-step reaction is merged into " one pot " reaction: in the first step, add triethylamine to make alkali, the III condensation of II and 1.3 times of molar weights obtains intermediate product 1-(4-benzyloxy phenyl)-2-[(4-benzyloxy phenyl) amino] acetone (IV), without separation, there is Bischler-Mohlau indoles ring closure reaction with the III of 1.5 times of molar weights that again add and generate product I in IV.Although this route is merged into two-step reaction " one pot ", simplified operation, but in order to remove excessive III and impurity, post-processing step is loaded down with trivial details, gained solid crude product need repeatedly be pulled an oar to wash and just can be obtained purer product I, yield lower (55%) in methanol/ether.
Route three (WO2008098527):
This route taking 2-bromo-(4-benzyloxy phenyl) acetone (II), to benzyloxy aniline hydrochloride (III) as starting raw material (to the consumption of benzyloxy aniline hydrochloride (III) be 2-bromo-(4-benzyloxy phenyl) acetone (II) 1.1-1.2 doubly), make solvent with alcohol (ethanol, Virahol etc.), condensation obtains intermediate 1-(4-benzyloxy phenyl)-2-[(4-benzyloxy phenyl) amino] acetone (IV), by after IV separation and purification, there is Bischler-Mohlau indoles ring closure reaction with the III of 0.2 times of molar weight and obtain product I in IV again.This route yield higher (two step total recovery 60%-75%), but intermediate product IV needs separation and purification, has increased operation, and whole piece route is succinct not.
Summary of the invention
Technical problem solved by the invention is, in order to overcome the defects such as existing 5-benzyloxy-2-(4-benzyloxy phenyl)-complicated process of preparation of 3-Methyl-1H-indole, complex operation, productive rate be low, to provide a kind of 5-benzyloxy-2-(4-benzyloxy phenyl) preparation method of-3-Methyl-1H-indole.This preparation method is simple to operate, and cost is low, has greatly simplified post-reaction treatment process, and purity is high, and reaction yield is high, is suitable for amplifying producing.
The present invention solves the problems of the technologies described above by the following technical programs:
The preparation method who the invention provides 5-benzyloxy-2-(4-benzyloxy phenyl)-3-Methyl-1H-indole, it comprises the following steps:
(1), in alcoholic solvent, under the effect of alkali, Compound I I and compound III are carried out to condensation reaction;
(2) reaction solution of step (1) is mixed with protonic acid, carries out Bischler-Mohlau indoles ring closure reaction;
In step (1), described alcoholic solvent is preferably one or more in propyl carbinol, isopropylcarbinol, n-propyl alcohol, Virahol and ethanol; Be more preferably one or more in propyl carbinol, isopropylcarbinol and n-propyl alcohol.Described alcoholic solvent is 5～15ml/g with the volume mass of Compound I I than preferably.
In step (1), described alkali is preferably mineral alkali and/or organic bases.Described mineral alkali is preferably one or more in salt of wormwood, sodium carbonate, sodium bicarbonate, saleratus, sodium hydroxide and potassium hydroxide; Described organic bases is preferably one or more in triethylamine, pyridine, 4-dimethylaminopyridine, morpholine and DIPEA.Described alkali is more preferably triethylamine.The mol ratio of described alkali and Compound I I is preferably (2:1)～(2.5:1).
In step (1), described Compound I I and the mol ratio of compound III are preferably (1:1)～(1:1.2).
In step (1), the temperature of described condensation reaction is preferably 75～160 DEG C, is more preferably 100～130 DEG C.The process of described condensation reaction can be monitored by this area conventional means (as TLC or HPLC), and while generally disappearance using Compound I I, as the terminal of reaction, the time of described condensation reaction is preferably 2～4 hours.
In the present invention, the reaction solution that described step (1) obtains can directly carry out step (2) without aftertreatment.
In step (2), before the reaction solution of step (1) is mixed with protonic acid, preferably carry out cooling.Described cooling preferably for the temperature of the reaction solution that naturally cools to described step (1) is 10～30 DEG C.
In step (2), described protonic acid is preferably mineral acid and/or organic acid.Described mineral acid is preferably one or more in hydrochloric acid, sulfuric acid and phosphoric acid, is more preferably hydrochloric acid; Described organic acid is preferably one or more in formic acid, acetic acid, propionic acid, oxalic acid, fumaric acid, toxilic acid, succsinic acid, tartrate, citric acid, propanedioic acid, methylsulfonic acid, Phenylsulfonic acid, tosic acid and tosic acid monohydrate, is more preferably tosic acid.The mol ratio of described protonic acid and Compound I I is preferably (0.05:1)～(0.3:1).
In step (2), the temperature of described Bischler-Mohlau indoles ring closure reaction is preferably 75～160 DEG C, is more preferably 100～130 DEG C.
The process of described Bischler-Mohlau indoles ring closure reaction can be monitored by this area conventional means (as TLC or HPLC), and the time of described Bischler-Mohlau indoles ring closure reaction is preferably 5～15 hours.
Wherein, after described Bischler-Mohlau indoles ring closure reaction finishes, can also carry out aftertreatment, be further purified Compound I.The mode of described aftertreatment can be the post processing mode of this area routine, preferably includes following steps: suction filtration, and dry.In the time that described alkali adopts mineral alkali, after suction filtration, preferably wash, drier.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can arbitrary combination, obtains the preferred embodiments of the invention.
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, the 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; In reaction solution, add acid, without again adding starting compound III, simplified operation, provide cost savings; Reaction product I directly separates out from reaction solvent, has greatly simplified post-reaction treatment process, and purity is high, and reaction yield is high, is suitable for amplifying producing.
Embodiment
Mode below by embodiment further illustrates the present invention, but does not therefore limit the present invention among described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example, according to ordinary method and condition, or selects 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 propyl carbinol (120ml), add triethylamine (12.2ml), be warming up to 118 DEG C of backflows, 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.Reaction solution is cooling, and suction filtration is dried to obtain white solid 15.2g, HPLC purity: 98%, and yield 90.5%.
1H-NMR(400MHz,d 6-DMSO)δ(ppm):7.798(br?s,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,-OCH 2-),5.153(s,2H,-OCH 2-),2.436(s,3H,-CH 3)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 isopropylcarbinol (120ml), add triethylamine (12.2ml), be warming up to 107 DEG C of backflows, after 3 hours, 2-bromo-(4-benzyloxy phenyl) acetone reacts completely; Add tosic acid monohydrate (1.7g), be warming up to 107 DEG C and continue reaction 14 hours.Reaction solution is cooling, and suction filtration is dried to obtain brown solid 14.4g, HPLC purity: 97%, and 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 Virahol (120ml), add pyridine (7.1ml), be warming up to 84 DEG C, after 4 hours, 2-bromo-(4-benzyloxy phenyl) acetone reacts completely; Add acetic acid (0.7ml) to continue reaction 15 hours.Reaction solution is cooling, and suction filtration is dried to obtain white solid 14.6g, HPLC purity: 96%, and 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 propyl carbinol (120ml), add morpholine (7.7ml), be warming up to 118 DEG C, after 3 hours, 2-bromo-(4-benzyloxy phenyl) acetone reacts completely; Add the vitriol oil (0.6ml), continue reaction 7 hours.Reaction solution is cooling, and suction filtration is dried to obtain white solid 14.7g, HPLC purity: 98%, and 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 propyl carbinol (120ml), add sodium carbonate (9.3g), be warming up to 118 DEG C of backflows, 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.Reaction solution is cooling, suction filtration, and gained solid washing (60ml), filters, and is 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 alcoholic solvent, under the effect of alkali, Compound I I and compound III are carried out to condensation reaction;
    (2) reaction solution of step (1) is mixed with protonic acid, carries out Bischler-Mohlau indoles ring closure reaction;
  2. 2. preparation method as claimed in claim 1, is characterized in that, in step (1), described alcoholic solvent is one or more in propyl carbinol, isopropylcarbinol, n-propyl alcohol, Virahol and ethanol; Described alcoholic solvent is 5～15ml/g with the volume mass ratio of Compound I I.
  3. 3. preparation method as claimed in claim 1, it is characterized in that, in step (1), described alkali is mineral alkali and/or organic bases, described mineral alkali is one or more in salt of wormwood, sodium carbonate, sodium bicarbonate, saleratus, sodium hydroxide and potassium hydroxide, described organic bases is one or more in triethylamine, pyridine, 4-dimethylaminopyridine, morpholine and DIPEA.
  4. 4. preparation method as claimed in claim 1, is characterized in that, the mol ratio of described alkali and Compound I I is (2:1)～(2.5:1).
  5. 5. preparation method as claimed in claim 1, is characterized in that, in step (1), described Compound I I and the mol ratio of compound III are (1:1)～(1:1.2).
  6. 6. preparation method as claimed in claim 1, is characterized in that, in step (1), the temperature of described condensation reaction is 75～160 DEG C; In step (2), the temperature of described Bischler-Mohlau indoles ring closure reaction is 75～160 DEG C.
  7. 7. preparation method as claimed in claim 6, is characterized in that, in step (1), the temperature of described condensation reaction is 100～130 DEG C; In step (2), the temperature of described Bischler-Mohlau indoles ring closure reaction is 100～130 DEG C.
  8. 8. preparation method as claimed in claim 1, it is characterized in that, in step (2), carry out before the reaction solution of step (1) is mixed with protonic acid coolingly, the temperature that described being cooled to naturally cools to the reaction solution of described step (1) is 10～30 DEG C.
  9. 9. preparation method as claimed in claim 1, is characterized in that, in step (2), described protonic acid is mineral acid and/or organic acid; Described mineral acid is one or more in hydrochloric acid, sulfuric acid and phosphoric acid; Described organic acid is one or more in formic acid, acetic acid, propionic acid, oxalic acid, fumaric acid, toxilic acid, succsinic acid, tartrate, citric acid, propanedioic acid, methylsulfonic acid, Phenylsulfonic acid, tosic acid and tosic acid monohydrate.
  10. 10. preparation method as claimed in claim 1, is characterized in that, the mol ratio of described protonic acid and Compound I I is (0.05:1)～(0.3:1).
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Cited By (1)

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Publication number Priority date Publication date Assignee Title
CN110627704A (en) * 2018-06-21 2019-12-31 艾瑞吉瑞股份公司 Preparation method of bazedoxifene

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110627704A (en) * 2018-06-21 2019-12-31 艾瑞吉瑞股份公司 Preparation method of bazedoxifene
US10844047B2 (en) 2018-06-21 2020-11-24 Erregierre S.P.A. Process for the preparation of bazedoxifene
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