CN103739540A - Method for preparing bazedoxifene acetate intermediate - Google Patents
Method for preparing bazedoxifene acetate intermediate Download PDFInfo
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- CN103739540A CN103739540A CN201410025111.8A CN201410025111A CN103739540A CN 103739540 A CN103739540 A CN 103739540A CN 201410025111 A CN201410025111 A CN 201410025111A CN 103739540 A CN103739540 A CN 103739540A
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- QYAODHFJFSYEMK-UHFFFAOYSA-N CC(c1ccccc1)Oc(cc1)ccc1N Chemical compound CC(c1ccccc1)Oc(cc1)ccc1N QYAODHFJFSYEMK-UHFFFAOYSA-N 0.000 description 1
- FLPJVCMIKUWSDR-UHFFFAOYSA-N NC(COc1ccc(C=O)cc1)=O Chemical compound NC(COc1ccc(C=O)cc1)=O FLPJVCMIKUWSDR-UHFFFAOYSA-N 0.000 description 1
- FHIZOXPYIZDXFG-UHFFFAOYSA-N NC(COc1ccc(CNc(cc2)ccc2OCc2ccccc2)cc1)=O Chemical compound NC(COc1ccc(CNc(cc2)ccc2OCc2ccccc2)cc1)=O FHIZOXPYIZDXFG-UHFFFAOYSA-N 0.000 description 1
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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
Abstract
The invention discloses a method for preparing a bazedoxifene acetate intermediate. The preparation method comprises the following steps: 1, condensing 4-hydroxybenzaldehyde S01 and alkylate S02 to prepare a 4-formyl phenoxy derivative M01; 2, performing reduction and ammoniation on the 4-formyl phenoxy derivative M01 and 4-benzyloxyaniline S03 to prepare an N-(4-benzyl)-4-benzyloxyaniline derivative M02; and 3, performing ring formation on the N-(4-benzyl)-4-benzyloxyaniline derivative M02 and 4'-benzyloxy-2-bromopropiophenone S04 to prepare a 5-benzyloxy-2-(4-(benzyloxyphenyl)-3-methyl-1H-indol derivative M03.
Description
Technical field
The present invention relates to technical field of medicine synthesis, particularly, the present invention relates to the intermediate synthetic method for the treatment of or prevention postmenopausal osteoporosis medicine bazedoxifene acetate.
Background technology
Bazedoxifene acetate (Bazedoxifene Acetate), chemical name is: 1-[4-(2-azepan-1-base-oxyethyl group)-benzyl]-2-(4-hydroxyl-phenyl)-3-Methyl-1H-indole-5-phenol acetate, its structure is as follows:
Bazedoxifene acetate (Bazedoxifene Acetate), is the selective estrogen receptor modulators class medicine of Ligand company and Wyeth, the cooperative development of Almirall company, and ratify first in April, 2009 in Europe, and commodity are called " Conbriza ".
Preclinical test data show, WAY 140424 has more target activity than other selective estrogen receptor modulatorss known today (SERMs), are " the bests of like product " so far.Clinical study shows, aspect increasing bone density and reducing risk of bone fracture, is significantly better than placebo, and WAY 140424 do not stimulate uterus and mammary gland cell, so can not cause uterine endometrium and cyclomastopathy, and security is good.Postmenopausal osteoporotic patients group is huge, and its harm causing should not be underestimated.WAY 140424 is compared with similar drugs, has good pharmacological effect and security advantages, has wide market outlook.
The bazedoxifene acetate synthetic method of bibliographical information mainly contains following six kinds of methods at present, is described below respectively:
Method 1, with reference to CN1106383C, synthetic route is as follows.The weak point of this patent is: synthetic route step is many; The upper substitution reaction productive rate of three-step reaction indoles N is low; There is potential safety hazard in LAH and NaH; The impurity that the 6th step a word used for translation encircles modification reaction generation heptan is difficult for removing, and increases finished product purifying difficulty.
Method 2, with reference to CN100339371C, synthetic route is as follows.The weak point of this patent is: sodium borohydride and sodium hydrogen exist potential safety hazard; A word used for translation heptan, ring was brought into from starting material, later reaction and dry rare gas element or the antioxidant protection of all needing while existing if any free alkali.
Method 3, with reference to CN102690225A, synthetic route is as follows.The weak point of this patent is: a word used for translation ring in heptan starts to bring into from the first step reaction, because the N on a word used for translation ring in heptan easily introduces new impurity; The last two steps reaction yield is low.
Method 4, with reference to US2012330008A1, synthetic route is as follows, in this patent, connect a word used for translation heptan ring and the exchange of palladium hydrocarbonize debenzylation two-step reaction after protected equally.The weak point of this patent is: the difficult buying of starting material price.
Method 5, with reference to CN102395561A, synthetic route is as follows.The weak point of this patent is: the 4th and the 5th step reaction yield is low.
Method 6, with reference to CN102395561A, synthetic route is as follows.The weak point of this patent is: step is more.
In above method, synthetic method 3 starts a word used for translation ring in heptan to bring into from the first step reaction, and because the N on a word used for translation ring in heptan easily introduces new impurity, so the introducing of a word used for translation ring in heptan should not be placed on route first half.If ring in a word used for translation heptan can be introduced in the back and can be avoided the side reaction on a word used for translation ring in heptan in intermediate preparation process, so we adopt CN1106383C on this basis, and the method in CN102395561A is now prepared WAY 140424 intermediate:
Then with this intermediate, prepare bazedoxifene acetate, the impurity effect of having avoided the too early introducing of a word used for translation ring in heptan to bring proposes new preparation method simultaneously, improves yield, purity so that in next step reaction, obtain purer, end product that quality is more excellent.
Summary of the invention
The object of the invention is to disclose a kind of preparation method of bazedoxifene acetate intermediate of novelty.
Another object of the present invention is to disclose the application in preparing bazedoxifene acetate of the midbody compound that uses in bazedoxifene acetate preparation process.
Suc as formula a preparation method for the bazedoxifene acetate intermediate of M03,
R wherein
1for cyano group, amide group, C
1-C
8alkyl chain ester group, C
1-C
8alkyl chain ketone group, the amino with protecting group, halogen; It is characterized in that, said method comprising the steps of:
Step Isosorbide-5-Nitrae-hydroxy benzaldehyde S01 and alkylide S02 carry out condensation reaction and obtain 4-formyl radical phenoxy group analog derivative M01 under alkaline condition,
R wherein
1as previously mentioned, R
2for halogen, carboxylic acid halides;
This step alkali used is salt of wormwood, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, triethylamine, Tributylamine; Reaction solvent is acetonitrile, propionitrile, ethyl acetate, propyl acetate, tetrahydrofuran (THF); Temperature of reaction is 0-70 ℃, with 40-55 ℃ of optimum; Reaction times was 1-48 hour, with 4-7 hour optimum.
Step 2,4-formaldehyde phenyl alkyl ether M01 and 4-benzyloxy-aniline S03 carry out reduction amination and obtain N-(4-phenmethyl)-4-benzyloxy-aniline analog derivative M02,
This step reductive agent used is sodium triacetoxy borohydride or sodium borohydride; Temperature of reaction is 0-70 ℃, with 30-35 ℃ of optimum; Reaction solvent is C
1-C
4alcohols, tetrahydrofuran (THF), methylene dichloride, toluene or dimethylbenzene; The mol ratio of 4-formaldehyde phenyl alkyl ether M01,4-benzyloxy-aniline S03 and reductive agent is 1:1:1～10, and wherein the ratio of reductive agent is with 2～3 optimums; Reaction times was 1-48 hour, with 3-6 hour optimum.
Step 3, N-(4-phenmethyl)-4-benzyloxy-aniline analog derivative M02 and 4 '-benzyloxy-2-brom-acetophenone S04 carry out annulation and obtain 5-benzyloxy-2-(4-(benzyloxy under alkaline condition) phenyl)-3-Methyl-1H-indole derivative M03,
This step alkali used is salt of wormwood, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, triethylamine, Tributylamine; Solvent for use is DMF, N,N-dimethylacetamide, toluene, dimethylbenzene or dimethyl sulfoxide (DMSO); Temperature of reaction is 30-150 ℃, with 100-130 ℃ of optimum; Reaction times was 1-48 hour, with 3-6 hour optimum.
Preferably, wherein,
Described in step 1, alkali is salt of wormwood, sodium carbonate, sodium bicarbonate, sodium hydroxide, and reaction solvent is acetonitrile, tetrahydrofuran (THF);
Described in step 2, reductive agent is sodium borohydride, and reaction solvent is C
1-C
4alcohols;
Described in step 3, alkali is sodium hydroxide, triethylamine, Tributylamine, and reaction solvent is DMF, N,N-dimethylacetamide.
R described in step 1
1for cyano group, amide group, C
1-C
8alkyl chain ester group, halogen; R
2for fluorine, chlorine, bromine, iodine.It is preferred,
Described in step 1, temperature of reaction is 40-55 ℃; Reaction times is 4-7 hour, and described alkali is salt of wormwood, and reaction solvent is acetonitrile, described R
1for C
1-C
8alkyl chain ester group, R
2for bromine;
Described in step 2, temperature of reaction is 30-35 ℃, and the reaction times is 3-6 hour, and described reductive agent is sodium borohydride, and reaction solvent is ethanol,
Described in step 3, temperature of reaction is 100-130 ℃, and the reaction times is 3-6 hour, and described alkali is triethylamine, and reaction solvent is DMF.
Described R
1for C
1-C
8alkyl chain ester group, wherein R
1for being ethyl acetate, R
2for bromine;
Most preferred, preparation method of the present invention is as follows:
4-(formyl radical phenoxy group) preparation of-ethyl acetate
In 500ml there-necked flask, add p-Hydroxybenzaldehyde (24.4g, 0.2mol), 2-ethyl bromoacetate (33.4g, 0.2mol) and salt of wormwood (55.2g, 0.4mol), then add 300ml acetonitrile, stirring reaction 5h at 50 ℃.After cool to room temperature, filter away insolubles, filtrate sylvite is revolved to steaming, residual molten thing dissolves with 200ml methylene dichloride, washes 3 times, and anhydrous magnesium sulfate drying, filters, and filtrate is revolved steaming, after crude product is dry, obtains product;
N-(4-(ethyl acetate ether) phenmethyl) preparation of-4-benzyloxy-aniline
In 500ml there-necked flask, add 300ml ethanol, 4-benzyloxy-aniline (29.8g; 0.15mol) with 4-(formyl radical phenoxy group)-ethyl acetate (31.2g; 0.15mol); after stirring; solution is cooled to 0-5 ℃, portion-wise addition sodium borohydride (14.0g, 0.37mol); added rear reaction solution and naturally risen to room temperature, 25 ℃ of stirring reaction 4h.Reaction finishes rear solution and is cooled to 0-5 ℃, in solution, slowly add the 100ml aqueous solution, added rear 0-5 ℃ stirring reaction 2 hours, revolve and evaporate most of ethanol, with methylene dichloride, water is extracted, merging organic phase washes 3 with water and washes, anhydrous magnesium sulfate drying, filter, filtrate revolving steamed to obtain crude product, after being dried, obtains product;
1-(4-(ethyl acetate ether) the phenmethyl)-5-benzyloxy-2-(4-(benzyloxy) phenyl) preparation of-3-Methyl-1H-indole
In 100ml single port bottle, add 20mlN, dinethylformamide, N-(4-(ethyl acetate ether) phenmethyl)-4-benzyloxy-aniline (19.6g, 0.05mol), 4 '-benzyloxy-2-brom-acetophenone (16.0g, 0.05mol) with 5.7g triethylamine, be stirred and heated to 120 ℃ of reactions 6 hours.After reaction finishes, be cooled to 0-5 ℃ to be poured in 100ml frozen water, stir 1 hour, solution is extracted with ethyl acetate, and after washing and drying, crude product is dried to obtain product.M03 compound of the present invention is further introduced a word used for translation by conventional synthetic method and is encircled heptan, and then get rid of benzyloxy and obtain WAY 140424, as CN1106383C, the following methods in CN102395561A:
Advantage of the present invention is as follows:
The present invention and above-mentioned CN1106383C, the intermediate preparation method in CN102395561A patent compares, and advantage of the present invention is as follows:
The impurity effect of having avoided the too early introducing of a word used for translation ring in heptan to bring proposes new preparation method simultaneously, improves yield and purity, to obtain the end product of high purity and high yield in next step reaction.
Below data are proved by experiment:
The intermediate M03 of gained can introduce a word used for translation by conventional synthetic method and encircle heptan, then gets rid of benzyloxy and obtains WAY 140424.
For the advantage of proof the inventive method, spy provides following detection data:
Intermediate yield prepared by the embodiment of the present invention 1 method is high, and purity is high, and impurity 1-3 content is low.
Embodiment
By the following examples, can conduct further description the present invention, yet scope of the present invention is not confined to following embodiment.
Embodiment 1
4-(formyl radical phenoxy group) preparation of-ethyl acetate
In 500ml there-necked flask, add p-Hydroxybenzaldehyde (24.4g, 0.2mol), 2-ethyl bromoacetate (33.4g, 0.2mol) and salt of wormwood (55.2g, 0.4mol), then add 300ml acetonitrile, stirring reaction 5h at 50 ℃.After cool to room temperature, filter away insolubles, filtrate sylvite is revolved to steaming, residual molten thing dissolves with 200ml methylene dichloride, washes 3 times, and anhydrous magnesium sulfate drying, filters, and filtrate is revolved steaming, after crude product is dry, obtains product 37.98g, productive rate 91.3%.
N-(4-(ethyl acetate ether) phenmethyl) preparation of-4-benzyloxy-aniline
In 500ml there-necked flask, add 300ml ethanol, 4-benzyloxy-aniline (29.8g; 0.15mol) with 4-(formyl radical phenoxy group)-ethyl acetate (31.2g; 0.15mol); after stirring; solution is cooled to 0-5 ℃, portion-wise addition sodium borohydride (14.0g, 0.37mol); added rear reaction solution and naturally risen to room temperature, 25 ℃ of stirring reaction 4h.Reaction finishes rear solution and is cooled to 0-5 ℃, in solution, slowly add the 100ml aqueous solution, added rear 0-5 ℃ stirring reaction 2 hours, revolved and evaporate most of ethanol, with methylene dichloride, water has been extracted, merging organic phase washes 3 with water and washes, anhydrous magnesium sulfate drying, filters, and filtrate revolving steamed to obtain crude product, after dry, obtain product 36.04g, productive rate 75.2%.
1-(4-(ethyl acetate ether) the phenmethyl)-5-benzyloxy-2-(4-(benzyloxy) phenyl) preparation of-3-Methyl-1H-indole
In 100ml single port bottle, add 20mlN, dinethylformamide, N-(4-(ethyl acetate ether) phenmethyl)-4-benzyloxy-aniline (19.6g, 0.05mol), 4 '-benzyloxy-2-brom-acetophenone (16.0g, 0.05mol) with 5.7g triethylamine, be stirred and heated to 120 ℃ of reactions 6 hours.After reaction finishes, be cooled to 0-5 ℃ to be poured in 100ml frozen water, stir 1 hour, solution is extracted with ethyl acetate, and after washing and drying, crude product is dried to obtain product 20.56g, yield 67.2%.
Embodiment 2
2-(4-formyl radical phenoxy group) preparation of-acetonitrile
In 500ml there-necked flask, add p-Hydroxybenzaldehyde (24.4g, 0.2mol), 2-bromoacetonitrile (24g, 0.2mol) and salt of wormwood (55.2g, 0.4mol), then add 300ml acetonitrile, stirring reaction 5h at 50 ℃.After cool to room temperature, filter away insolubles, filtrate sylvite is revolved to steaming, residual molten thing dissolves with 200ml methylene dichloride, washes 3 times, and anhydrous magnesium sulfate drying, filters, and filtrate is revolved steaming, after crude product is dry, obtains product 28.72g, productive rate 89.1%.
N-(4-(acetonitrile ether) phenmethyl) preparation of-4-benzyloxy-aniline
In 500ml there-necked flask, add 300ml ethanol, 4-benzyloxy-aniline (29.8g; 0.15mol) with 2-(4-formyl radical phenoxy group)-acetonitrile (24.15g; 0.15mol); after stirring; solution is cooled to 0-5 ℃, portion-wise addition sodium borohydride (14.0g, 0.37mol); added rear reaction solution and naturally risen to room temperature, 25 ℃ of stirring reaction 4h.Reaction finishes rear solution and is cooled to 0-5 ℃, in solution, slowly add the 100ml aqueous solution, added rear 0-5 ℃ stirring reaction 2 hours, revolved and evaporate most of ethanol, with methylene dichloride, water has been extracted, merging organic phase washes 3 with water and washes, anhydrous magnesium sulfate drying, filters, and filtrate revolving steamed to obtain crude product, after dry, obtain product 35.18g, productive rate 68.1%.
1-(4-(acetonitrile ether) the phenmethyl)-5-benzyloxy-2-(4-(benzyloxy) phenyl) preparation of-3-Methyl-1H-indole
In 100ml single port bottle, add 20mlN, dinethylformamide, N-(4-(acetonitrile ether) phenmethyl)-4-benzyloxy-aniline (17.2g, 0.05mol), 4 '-benzyloxy-2-brom-acetophenone (16.0g, 0.05mol) and 5.7g triethylamine, be stirred and heated to 120 ℃ of reactions 6 hours.After reaction finishes, be cooled to 0-5 ℃ to be poured in 100ml frozen water, stir 1 hour, solution is extracted with ethyl acetate, and after washing and drying, crude product is dried to obtain product 17.73g, yield 62.8%.
Embodiment 3
Amide group
4-(formyl radical phenoxy group) preparation of-ethanamide
In 500ml there-necked flask, add p-Hydroxybenzaldehyde (24.4g, 0.2mol), 2-bromoacetamide (27.6g, 0.2mol) and salt of wormwood (55.2g, 0.4mol), then add 300ml acetonitrile, stirring reaction 5h at 50 ℃.After cool to room temperature, filter away insolubles, filtrate sylvite is revolved to steaming, residual molten thing dissolves with 200ml methylene dichloride, washes 3 times, and anhydrous magnesium sulfate drying, filters, and filtrate is revolved steaming, after crude product is dry, obtains product 27.31g, productive rate 76.3%.
The preparation of N-(4-(ethanamide) phenmethyl)-4-benzyloxy-aniline
In 500ml there-necked flask, add 200ml ethanol, 4-benzyloxy-aniline (19.9g; 0.10mol) with 4-(formyl radical phenoxy group)-ethanamide (14.3g; 0.08mol); after stirring; solution is cooled to 0-5 ℃, portion-wise addition sodium borohydride (7.57g, 0.20mol); added rear reaction solution and naturally risen to room temperature, 25 ℃ of stirring reaction 4h.Reaction finishes rear solution and is cooled to 0-5 ℃, in solution, slowly add the 100ml aqueous solution, added rear 0-5 ℃ stirring reaction 2 hours, revolved and evaporate most of ethanol, with methylene dichloride, water has been extracted, merging organic phase washes 3 with water and washes, anhydrous magnesium sulfate drying, filters, and filtrate revolving steamed to obtain crude product, after dry, obtain product 13.10g, productive rate 45.2%.
1-(4-(ethanamide) the phenmethyl)-5-benzyloxy-2-(4-(benzyloxy) phenyl) preparation of-3-Methyl-1H-indole
In 50ml single port bottle, add 12mlN, dinethylformamide, N-(4-(ethanamide) phenmethyl)-4-benzyloxy-aniline (10.9g, 0.03mol), 4 '-benzyloxy-2-brom-acetophenone (9.6g, 0.03mol) and 3.42g triethylamine, be stirred and heated to 120 ℃ of reactions 6 hours.After reaction finishes, be cooled to 0-5 ℃ to be poured in 50ml frozen water, stir 1 hour, solution is extracted with ethyl acetate, and after washing and drying, crude product is dried to obtain product 10.70g, yield 61.2%.
Embodiment 4
4-(formyl radical phenoxy group) preparation of-methyl acetate
In 500ml there-necked flask, add p-Hydroxybenzaldehyde (24.4g, 0.2mol), 2-methyl bromoacetate (30.6g, 0.2mol) and salt of wormwood (55.2g, 0.4mol), then add 300ml acetonitrile, stirring reaction 5h at 50 ℃.After cool to room temperature, filter away insolubles, filtrate sylvite is revolved to steaming, residual molten thing dissolves with 200ml methylene dichloride, washes 3 times, and anhydrous magnesium sulfate drying, filters, and filtrate is revolved steaming, after crude product is dry, obtains product 34.96g, productive rate 90.1%.
N-(4-(methyl acetate ether) phenmethyl) preparation of-4-benzyloxy-aniline
In 500ml there-necked flask, add 300ml ethanol, 4-benzyloxy-aniline (29.8g; 0.15mol) with 4-(formyl radical phenoxy group)-methyl acetate (29.1g; 0.15mol); after stirring; solution is cooled to 0-5 ℃, portion-wise addition sodium borohydride (14.0g, 0.37mol); added rear reaction solution and naturally risen to room temperature, 25 ℃ of stirring reaction 4h.Reaction finishes rear solution and is cooled to 0-5 ℃, in solution, slowly add the 100ml aqueous solution, added rear 0-5 ℃ stirring reaction 2 hours, revolved and evaporate most of ethanol, with methylene dichloride, water has been extracted, merging organic phase washes 3 with water and washes, anhydrous magnesium sulfate drying, filters, and filtrate revolving steamed to obtain crude product, after dry, obtain product 37.02g, productive rate 65.4%.
1-(4-(methyl acetate ether) the phenmethyl)-5-benzyloxy-2-(4-(benzyloxy) phenyl) preparation of-3-Methyl-1H-indole
In 100ml single port bottle, add 36mlN, dinethylformamide, N-(4-(methyl acetate ether) phenmethyl)-4-benzyloxy-aniline (33.9g, 0.09mol), 4 '-benzyloxy-2-brom-acetophenone (28.8g, 0.09mol) with 10.3g triethylamine, be stirred and heated to 120 ℃ of reactions 6 hours.After reaction finishes, be cooled to 0-5 ℃ to be poured in 150ml frozen water, stir 1 hour, solution is extracted with ethyl acetate, and after washing and drying, crude product is dried to obtain product 33.94g, yield 62.8%.
Claims (8)
1. suc as formula the preparation method of the bazedoxifene acetate intermediate of M03,
R wherein
1for cyano group, amide group, C
1-C
8alkyl chain ester group, C
1-C
8alkyl chain ketone group, the amino with protecting group, halogen; It is characterized in that, said method comprising the steps of:
Step Isosorbide-5-Nitrae-hydroxy benzaldehyde S01 and alkylide S02 carry out condensation reaction and obtain 4-formyl radical phenoxy group analog derivative M01 under alkaline condition,
R wherein
1as previously mentioned, R
2for halogen, carboxylic acid halides;
This step alkali used is salt of wormwood, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, triethylamine, Tributylamine; Reaction solvent is acetonitrile, propionitrile, ethyl acetate, propyl acetate, tetrahydrofuran (THF); Temperature of reaction is 0-70 ℃, and the reaction times is 1-48 hour.
Step 2,4-formaldehyde phenyl alkyl ether M01 and 4-benzyloxy-aniline S03 carry out reduction amination and obtain N-(4-phenmethyl)-4-benzyloxy-aniline analog derivative M02,
This step reductive agent used is sodium triacetoxy borohydride or sodium borohydride; Temperature of reaction is 0-70 ℃, with 30-35 ℃ of optimum; Reaction solvent is C
1-C
4alcohols, tetrahydrofuran (THF), methylene dichloride, toluene or dimethylbenzene; The mol ratio of 4-formaldehyde phenyl alkyl ether M01,4-benzyloxy-aniline S03 and reductive agent is 1:1:1～10; Reaction times is 1-48 hour.
Step 3, N-(4-phenmethyl)-4-benzyloxy-aniline analog derivative M02 and 4 '-benzyloxy-2-brom-acetophenone S04 carry out annulation and obtain 5-benzyloxy-2-(4-(benzyloxy under alkaline condition) phenyl)-3-Methyl-1H-indole derivative M03,
This step alkali used is salt of wormwood, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, triethylamine, Tributylamine; Solvent for use is DMF, N,N-dimethylacetamide, toluene, dimethylbenzene or dimethyl sulfoxide (DMSO); Temperature of reaction is 30-150 ℃; Reaction times is 1-48 hour.
2. preparation method as described in claim 1, wherein,
Described in step 1, temperature of reaction is 40-55 ℃; Reaction times is 4-7 hour.
Described in step 2, temperature of reaction is 30-35 ℃, and the reaction times is 3-6 hour.
Described in step 3, temperature of reaction is 100-130 ℃, and the reaction times is 3-6 hour.
3. preparation method as described in claim 1, wherein,
Described in step 1, alkali is salt of wormwood, sodium carbonate, sodium bicarbonate, sodium hydroxide, and reaction solvent is acetonitrile, tetrahydrofuran (THF); ,
Described in step 2, reductive agent is sodium borohydride, and reaction solvent is C
1-C
4alcohols,
Described in step 3, alkali is sodium hydroxide, triethylamine, Tributylamine, and reaction solvent is DMF, N,N-dimethylacetamide.
4. preparation method as described in claim 1, wherein,
R described in step 1
1for cyano group, amide group, C
1-C
8alkyl chain ester group, halogen; R
2for fluorine, chlorine, bromine, iodine.
5. preparation method as described in claim 1, wherein,
Described in step 1, temperature of reaction is 40-55 ℃; Reaction times is 4-7 hour, and described alkali is salt of wormwood, and reaction solvent is acetonitrile, described R
1for C
1-C
8alkyl chain ester group; R
2for bromine
Described in step 2, temperature of reaction is 30-35 ℃, and the reaction times is 3-6 hour, and described reductive agent is sodium borohydride, and reaction solvent is ethanol,
Described in step 3, temperature of reaction is 100-130 ℃, and the reaction times is 3-6 hour, and described alkali is triethylamine, and reaction solvent is DMF.
6. preparation method as described in claim 1, wherein,
Described in step 1, temperature of reaction is 40-55 ℃; Reaction times is 4-7 hour, and described alkali is salt of wormwood, and reaction solvent is acetonitrile, described R
1for ethyl acetate base; R
2for bromine.
7. preparation method as described in claim 1, wherein,
Described in step 2, the mol ratio of 4-formaldehyde phenyl alkyl ether M01,4-benzyloxy-aniline S03 and reductive agent is 1:1:2-3.
8. preparation method as described in claim 1, is characterized in that, step is as follows:
4-(formyl radical phenoxy group) preparation of-ethyl acetate
In 500ml there-necked flask, add p-Hydroxybenzaldehyde (24.4g, 0.2mol), 2-ethyl bromoacetate (33.4g, 0.2mol) and salt of wormwood (55.2g, 0.4mol), then add 300ml acetonitrile, stirring reaction 5h at 50 ℃.After cool to room temperature, filter away insolubles, filtrate sylvite is revolved to steaming, residual molten thing dissolves with 200ml methylene dichloride, washes 3 times, and anhydrous magnesium sulfate drying, filters, and filtrate is revolved steaming, after crude product is dry, obtains product;
N-(4-(ethyl acetate ether) phenmethyl) preparation of-4-benzyloxy-aniline
In 500ml there-necked flask, add 300ml ethanol, 4-benzyloxy-aniline (29.8g; 0.15mol) with 4-(formyl radical phenoxy group)-ethyl acetate (31.2g; 0.15mol); after stirring; solution is cooled to 0-5 ℃, portion-wise addition sodium borohydride (14.0g, 0.37mol); added rear reaction solution and naturally risen to room temperature, 25 ℃ of stirring reaction 4h.Reaction finishes rear solution and is cooled to 0-5 ℃, in solution, slowly add the 100ml aqueous solution, added rear 0-5 ℃ stirring reaction 2 hours, revolve and evaporate most of ethanol, with methylene dichloride, water is extracted, merging organic phase washes 3 with water and washes, anhydrous magnesium sulfate drying, filter, filtrate revolving steamed to obtain crude product, after being dried, obtains product;
1-(4-(ethyl acetate ether) the phenmethyl)-5-benzyloxy-2-(4-(benzyloxy) phenyl) preparation of-3-Methyl-1H-indole
In 100ml single port bottle, add 20mlN, dinethylformamide, N-(4-(ethyl acetate ether) phenmethyl)-4-benzyloxy-aniline (19.6g, 0.05mol), 4 '-benzyloxy-2-brom-acetophenone (16.0g, 0.05mol) with 5.7g triethylamine, be stirred and heated to 120 ℃ of reactions 6 hours.After reaction finishes, be cooled to 0-5 ℃ to be poured in 100ml frozen water, stir 1 hour, solution is extracted with ethyl acetate, and after washing and drying, crude product is dried to obtain product.
Priority Applications (1)
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| CN104569202A (en) * | 2015-01-05 | 2015-04-29 | 万特制药(海南)有限公司 | Method for separating and testing bazedoxifene and related substances of bazedoxifene |
| CN112110845A (en) * | 2019-06-21 | 2020-12-22 | 中国科学院福建物质结构研究所 | Synthesis method of bazedoxifene and analogues thereof |
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| CN112110845A (en) * | 2019-06-21 | 2020-12-22 | 中国科学院福建物质结构研究所 | Synthesis method of bazedoxifene and analogues thereof |
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