CN101812002A - Synthesizing process of 4-methoxy-alpha-[(3-methoxyphenyl)sulfo]-acetophenone - Google Patents
Synthesizing process of 4-methoxy-alpha-[(3-methoxyphenyl)sulfo]-acetophenone Download PDFInfo
- Publication number
- CN101812002A CN101812002A CN201010151857A CN201010151857A CN101812002A CN 101812002 A CN101812002 A CN 101812002A CN 201010151857 A CN201010151857 A CN 201010151857A CN 201010151857 A CN201010151857 A CN 201010151857A CN 101812002 A CN101812002 A CN 101812002A
- Authority
- CN
- China
- Prior art keywords
- methoxy
- sulfo
- methoxyacetophenone
- alpha
- phenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a synthesizing process of 4-methoxy-alpha-[(3-methoxyphenyl)sulfo]-acetophenone, belonging to the synthesizing technique of medical intermediates. The synthesizing process comprises the following steps of dissolving alpha-bromo-4-methoxyphenyl-acetophenone in ethanol, and obtaining the 4-methoxy-alpha-[(3-methoxyphenyl)sulfo]-acetophenone by adding the mixed liquid of potassium hydroxide solution and 3-methoxy-thiophenol ethanol solution. The invention has the advantages of convenient operation, low cost, high purity and high yield rate.
Description
Technical field
The present invention relates to the synthesis technique of a kind of α-[(3-p-methoxy-phenyl) sulfo-]-4-methoxyacetophenone, belong to the synthetic technology of medicine intermediate.
Background technology
Raloxifene (English name: be a kind of osteoporosis remedy that gift comes company to develop raloxifene), go on the market in the U.S. that the sales volume of 2004-2008 remains on more than 1,000,000,000 dollars continuously the end of the year 1997.In the building-up process of this medicine, common synthetic route is to be starting raw material with 3-methoxybenzenethiol and alpha-brominated-4-methoxyacetophenone, makes through reactions such as condensation, cyclization, acidylate and demethylations.
Wherein α-[(3-p-methoxy-phenyl) sulfo-]-4-methoxyl group ethyl ketone is the intermediate product (as figure below) of the first step condensation reaction in the raloxifene preparation process:
When preparation α-[(3-p-methoxy-phenyl) sulfo-]-4-methoxyacetophenone intermediate, the preparation process condition of report is few.Wherein (US 6472531 for United States Patent (USP), US 5523416) reported method is: earlier 3-methoxybenzenethiol and potassium hydroxide water-soluble with ethanol in, with icy salt solution drop to 0 ℃ of gradation add solid alpha-brominated-the 4-methoxyacetophenone, add and be raised to room temperature reaction, solvent evaporated subsequently, ethyl acetate extraction, washing, drying, evaporated under reduced pressure get oily matter, get with refining methanol at last.The shortcoming of this technology is: (1) gradation is reinforced inhomogeneous, reinforced must under icy salt solution, the cooling, and the solid difficulty of adding is dissolved in the solution entirely, causes reaction not thorough, and impurity is more.(2) based on incomplete this reason of reaction, the aftertreatment complexity of reaction product need be used 2 kinds of novel solvents and extract and make with extra care, and causes yield to reduce, and cost increases, and the three wastes increase.
Synthesizing after the domestic also report improvement once, report as " pharmacy progress " the 5th phase in 2003: be dissolved in alpha-brominated-4-methoxyacetophenone in the ethyl acetate earlier, evenly be added drop-wise in the potassium hydroxide solution of 3-methoxybenzenethiol subsequently, though this method has solved reinforced simplification problem.But this technology still relates to solvent distillation, ethyl acetate extraction and refining methanol etc., and yield can not improve.And use ethanol and ethyl acetate mixed organic solvents, manufacturing cost is still too high.
Summary of the invention
The invention provides the synthesis technique of a kind of improved α-[(3-p-methoxy-phenyl) sulfo-]-4-methoxyacetophenone, easy to operate, cost is low, purity height, yield height.
The synthesis technique of α of the present invention-[(3-p-methoxy-phenyl) sulfo-]-4-methoxyacetophenone is dissolved into alpha-brominated-4-methoxyacetophenone in the ethanol earlier, and the mixed solution that adds potassium hydroxide solution and 3-methoxybenzenethiol ethanolic soln again makes.
Wherein:
Charge temperature is controlled to be 35-40 ℃, and temperature of reaction is a room temperature.
The concentration of the ethanolic soln of alpha-brominated-4-methoxyacetophenone is 5-30%g/ml.
The concentration of potassium hydroxide aqueous solution is 20-50%g/ml.
The concentration of 3-methoxybenzenethiol ethanolic soln is 30-80%g/ml.
The volume ratio of potassium hydroxide solution and 3-methoxybenzenethiol ethanolic soln is 1: 2-5.
Synthesis technique of the present invention has following beneficial effect:
Products therefrom can direct filtration or centrifugal, reduces solvent and uses, and have the following advantages:
(1) temperature of reaction 40 ℃ to carrying out between the room temperature, easy to operate, need not with icy salt solution cooling, evenly reinforced, it is homogeneous reaction that reaction is close to, reaction thoroughly, the yield height.
(2) because of entire reaction is thorough, need not ethyl acetate extraction and refining methanol, the content of products therefrom HPLC is all more than 99%, and the purity height economizes in raw materials again and production cost, and helps environmental protection, is more suitable in suitability for industrialized production.
Embodiment
The invention will be further described below in conjunction with embodiment.
Embodiment 1
Claim 8g potassium hydroxide in the triangular flask, the water that adds 15ml all dissolves solid, and other claims the ethanol adding triangular flask of 20g3-methoxyphenol and 30ml to stir.Add in the reaction flask 32.8g alpha-brominated-the 4-methoxyacetophenone, add 95% ethanol of 150ml, stir and be raised to 35-40 ℃, drips the above-mentioned solution for preparing, drip off this thermotonus of maintenance 0.5 hour.Drop to stirring at room reaction 12 hours subsequently.Filter out white solid, solid adds 300ml water, stirs 2 hours, filters and obtains the white powder solid, and drying under reduced pressure gets α-[(3-p-methoxy-phenyl) sulfo-]-4-methoxyacetophenone 38g, m.p.51-53 ℃, HPLC99.5%, yield 91% under the normal temperature.
Embodiment 2
Claim 5g potassium hydroxide in the triangular flask, the water that adds 20ml all dissolves solid, and other claims the ethanol adding triangular flask of 12.5g3-methoxyphenol and 30ml to stir.Add in the reaction flask 20.5g alpha-brominated-the 4-methoxyacetophenone, add 95% ethanol of 120ml, stir and be raised to 35-40 ℃, drips the above-mentioned solution for preparing, drip off this thermotonus of maintenance 0.5 hour.Drop to stirring at room reaction 12 hours subsequently.Filter out white solid, solid adds 200ml water, stirs 2 hours, filters and obtains the white powder solid, and drying under reduced pressure gets α-[(3-p-methoxy-phenyl) sulfo-]-4-methoxyacetophenone 24g, m.p.51-53 ℃, HPLC99.3%, yield 92% under the normal temperature.
Claims (6)
1. the synthesis technique of α-[(3-p-methoxy-phenyl) sulfo-]-4-methoxyacetophenone, it is characterized in that earlier alpha-brominated-4-methoxyacetophenone being dissolved in the ethanol, the mixed solution that adds potassium hydroxide solution and 3-methoxybenzenethiol ethanolic soln again makes.
2. the synthesis technique of α according to claim 1-[(3-p-methoxy-phenyl) sulfo-]-4-methoxyacetophenone is characterized in that charge temperature is 35-40 ℃, and temperature of reaction is a room temperature.
3. the synthesis technique of α according to claim 1 and 2-[(3-p-methoxy-phenyl) sulfo-]-4-methoxyacetophenone, the concentration that it is characterized in that the ethanolic soln of alpha-brominated-4-methoxyacetophenone is 5-30%g/ml.
4. the synthesis technique of α according to claim 3-[(3-p-methoxy-phenyl) sulfo-]-4-methoxyacetophenone, the concentration that it is characterized in that potassium hydroxide aqueous solution is 20-50%g/ml.
5. the synthesis technique of α according to claim 4-[(3-p-methoxy-phenyl) sulfo-]-4-methoxyacetophenone, the concentration that it is characterized in that 3-methoxybenzenethiol ethanolic soln is 30-80%g/ml.
6. the synthesis technique of α according to claim 4-[(3-p-methoxy-phenyl) sulfo-]-4-methoxyacetophenone is characterized in that the volume ratio of potassium hydroxide solution and 3-methoxybenzenethiol ethanolic soln is 1: 2-5.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010151857A CN101812002A (en) | 2010-04-16 | 2010-04-16 | Synthesizing process of 4-methoxy-alpha-[(3-methoxyphenyl)sulfo]-acetophenone |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010151857A CN101812002A (en) | 2010-04-16 | 2010-04-16 | Synthesizing process of 4-methoxy-alpha-[(3-methoxyphenyl)sulfo]-acetophenone |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101812002A true CN101812002A (en) | 2010-08-25 |
Family
ID=42619388
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201010151857A Pending CN101812002A (en) | 2010-04-16 | 2010-04-16 | Synthesizing process of 4-methoxy-alpha-[(3-methoxyphenyl)sulfo]-acetophenone |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101812002A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112174793A (en) * | 2020-10-14 | 2021-01-05 | 温州大学 | Method and ligand for breaking C-S bond of alpha-thioaryl ethanone compound |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4380635A (en) * | 1981-04-03 | 1983-04-19 | Eli Lilly And Company | Synthesis of acylated benzothiophenes |
| US5523416A (en) * | 1994-07-22 | 1996-06-04 | Eli Lilly And Company | Process for preparing 3-(4-aminoethoxy-benzoyl) benzo (B)-thiophenes |
| CN1871210A (en) * | 2003-10-20 | 2006-11-29 | 巴斯福股份公司 | Method for the production of dollar g(a)-(3-arylthio)-acetophenones |
-
2010
- 2010-04-16 CN CN201010151857A patent/CN101812002A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4380635A (en) * | 1981-04-03 | 1983-04-19 | Eli Lilly And Company | Synthesis of acylated benzothiophenes |
| US5523416A (en) * | 1994-07-22 | 1996-06-04 | Eli Lilly And Company | Process for preparing 3-(4-aminoethoxy-benzoyl) benzo (B)-thiophenes |
| CN1871210A (en) * | 2003-10-20 | 2006-11-29 | 巴斯福股份公司 | Method for the production of dollar g(a)-(3-arylthio)-acetophenones |
Non-Patent Citations (4)
| Title |
|---|
| 《精细化工中间体》 20061231 张艳林等 雷洛昔芬中间体4-甲氧基-alpha-[(3-甲氧基苯基)硫代]-苯乙酮含量的反相高效液相色谱测定 第65-67页 1-6 第36卷, 第6期 * |
| CHARLES D.JONES: "Antiestrogens.", 《J.MED.CHEM.》 * |
| 张艳林等: "雷洛昔芬中间体4-甲氧基-α-[(3-甲氧基苯基)硫代]-苯乙酮含量的反相高效液相色谱测定", 《精细化工中间体》 * |
| 陆涛等: "预防骨质疏松症药物盐酸雷洛昔芬的合成", 《药学进展》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112174793A (en) * | 2020-10-14 | 2021-01-05 | 温州大学 | Method and ligand for breaking C-S bond of alpha-thioaryl ethanone compound |
| CN112174793B (en) * | 2020-10-14 | 2023-03-28 | 温州大学 | Method and ligand for breaking C-S bond of alpha-thioaryl ethanone compound |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102503843B (en) | Preparation method for metoprolol salt | |
| CN111646917B (en) | Preparation method of iodobenzene para-amination compound promoted by m-chloroperoxybenzoic acid | |
| CN105152830B (en) | A kind of synthetic method of ketone compounds | |
| CN104557536B (en) | A kind of preparation method of monomethyl succinate | |
| CN102746170A (en) | Preparation method of dapoxetine | |
| CN104936939A (en) | Method for producing aromatic dihydroxy compound | |
| CN102875341A (en) | Synthetic method of benzaldehyde | |
| CN101812002A (en) | Synthesizing process of 4-methoxy-alpha-[(3-methoxyphenyl)sulfo]-acetophenone | |
| CN100391943C (en) | Prepn. of 3-position substituted indole derivative | |
| CN104774173B (en) | A kind of method that utilization presence of acidic ionic liquid catalyst prepares 5,6-tetrahydropyridine derivative | |
| CN100376555C (en) | Process for preparing diindolylmethane derivatives | |
| CN102408384B (en) | Improved synthesis method of quinocetone | |
| CN101717352B (en) | Method for synthesizing agmatine sulfate | |
| CN109251138A (en) | A kind of preparation method of all natural carbon source raspberry ketone | |
| CN104876932B (en) | A kind of efficient catalytic synthesizes the method for 2H indole [2,1 b] phthalazines 1,6,11 (13H) triketone | |
| CN109265330A (en) | A kind of preparation method of 4-(4-hydroxyphenyl)-2-butanone | |
| CN102786371A (en) | New method for producing alpha,beta-unsaturated carbonyl compounds by using one-pot condensation reaction | |
| CN102757390B (en) | Method for preparing 2-methoxy-4-diazanyl-5-fluoropyrimidine | |
| CN101665418B (en) | Methods for preparing E-3,5-dimethoxy-4'-oxhydryl diphenylethene and derivative thereof | |
| CN105237346B (en) | The preferential crystallization preparation method of chiral alpha benzyl carbinol | |
| CN111116339B (en) | Method for artificially synthesizing curcumin and derivatives thereof | |
| CN104326927B (en) | A kind of preparation method of 1-[2-amino-1-(4-methoxyphenyl) ethyl] Hexalin sulfate | |
| CN102911027A (en) | Method for preparing indanone | |
| CN108101740B (en) | Method for directly converting aromatic alkyne into chiral alcohol by one-pot method | |
| CN104876806A (en) | Novel method for synthesizing bisoprolol importance intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20100825 |