CN103483173A - Preparation method for intermediate (namely 1-(4-benzyloxy-phenyl)-2-bromo-propan-1-one) for bazedoxifene acetate - Google Patents
Preparation method for intermediate (namely 1-(4-benzyloxy-phenyl)-2-bromo-propan-1-one) for bazedoxifene acetate Download PDFInfo
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- CN103483173A CN103483173A CN201310436798.XA CN201310436798A CN103483173A CN 103483173 A CN103483173 A CN 103483173A CN 201310436798 A CN201310436798 A CN 201310436798A CN 103483173 A CN103483173 A CN 103483173A
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- benzyloxy
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
Abstract
The invention discloses a preparation method for an intermediate (namely 1-(4-benzyloxy-phenyl)-2-bromo-propan-1-one) for bazedoxifene acetate. The preparation method comprises the following steps: adding 1-(4-benzyloxy-phenyl)-2-propan-1-one and a metal bromine salt into an organic solvent, heating for reflux, and after completion of reaction, cooling to obtain a reaction solution; treating the reaction solution to obtain a liquid crude product, adding the liquid crude product into an organic solvent, heating for reflux for 0.5-2 hours, and after completion of reflux, treating to obtain a product. According to the preparation method, the easily obtained metal bromine salt substitutes for elementary bromine for bromination reaction, so that the selectivity of reaction is improved; the reaction condition is gentle, the selectivity is high, the intermediate (1-(4-benzyloxy-phenyl)-2-bromo-propan-1-one) for the bazedoxifene acetate is synthesized efficiently, and the yield and purity of the obtained product are high, so that the method is suitable for industrial production.
Description
Technical field
The invention belongs to the organic products preparing technical field, be specifically related to the preparation method of a kind of bazedoxifene acetate intermediate 1-(4-benzyloxy-phenyl)-2-bromopropyl-1-ketone.
Background technology
The key intermediate that 1-(4-benzyloxy-phenyl)-the 2-bromopropyl-1-ketone is acetic acid synthesized WAY 140424 is the important control point of acetic acid synthesized WAY 140424.Bazedoxifene acetate medicine former ground the preparation method that the ASTRAZENECA UK LIMITED of enterprise discloses a kind of this pharmaceutical intermediate, and the method be take bromine as brominated reagent, and acetic acid is that solvent is prepared.But bromine, as the brominated reagent poor selectivity, is difficult to control; As the solvent zero degree, time reaction is difficult to operation (being solid-state during the acetic acid zero degree) to acetic acid, is not suitable for industrial production.
Summary of the invention
The object of the present invention is to provide the preparation method of a kind of bazedoxifene acetate intermediate 1-(4-benzyloxy-phenyl)-2-bromopropyl-1-ketone.
For achieving the above object, the present invention adopts following technical scheme:
The preparation method of a kind of bazedoxifene acetate intermediate 1-(4-benzyloxy-phenyl)-2-bromopropyl-1-ketone comprises the following steps:
(1) 1-(4-benzyloxy-phenyl)-2-propyl group-1-ketone and metal bromate salt are added to reflux in organic solvent, TLC plate tracking monitor is complete to 1-(4-benzyloxy-phenyl)-2-propyl group-1-reactive ketone, stop heating, after reaction finishes, be cooled to room temperature (25 ℃) and obtain reaction solution;
(2) reaction solution treated (described treatment process is the sand core funnel suction filtration, then steams solvent in filtrate) obtains the liquid crude product, and the liquid crude product is added to reflux 0.5-2h in organic solvent, refluxes and finishes by processing and obtain product.
Wherein, the mass ratio of described 1-(4-benzyloxy-phenyl)-2-propyl group-1-ketone and metal bromate salt is 1: (1-10).
Reflux in aforesaid method step (2) after end, be cooled to below 0 ℃ and make product crystallization, filtering and washing, filter cake had been both product; Last filtrate again through refluxing, cooling, crystallization obtains surplus products.
In aforesaid method, described metal bromate salt is cupric bromide.
In aforesaid method, described organic solvent is chloroparaffin kind solvent, amine solvent or alcoholic solvent; Preferably, described organic solvent is methylene dichloride, 1,2-ethylene dichloride, chloroform, ethanol, ethyl acetate, methyl-formiate, one or more in ethyl formate, methyl acetate, DMF, DME, NMP; Wherein, the consumption of organic solvent is any ratio.
Synthetic route of the present invention is as follows:
The present invention adopts the metal bromate salt be easy to get to replace simple substance bromine to carry out bromination reaction, has improved the selectivity of reaction.The inventive method reaction conditions is gentle, high, high efficiency bazedoxifene acetate intermediate 1-(4-benzyloxy-phenyl)-2-bromopropyl-1-ketone that synthesized of selectivity, and the products obtained therefrom productive rate is high, purity good, is applicable to suitability for industrialized production.
The accompanying drawing explanation
The nucleus magnetic hydrogen spectrum figure that Fig. 1 is products obtained therefrom in embodiment.
Embodiment
Below in conjunction with embodiment, the present invention is described further, but protection scope of the present invention is not limited in this.
(1) add successively 24g1-(4-benzyloxy-phenyl)-2-propyl group-1-ketone, 45g CuBr in the 1L there-necked flask
2, 250 mL ethyl acetate, the 250mL chloroform, reflux, TLC plate tracking monitor to main raw material (1-(4-benzyloxy-phenyl)-2-propyl group-1-ketone) reacts completely, and stops heating, is cooled to room temperature (25 ℃), and reaction finishes to obtain reaction solution.
(2) reaction solution is through the sand core funnel suction filtration, filtrate steams solvent, obtain crude product brown oil 37.6g, add the 250mL dehydrated alcohol in crude product, the muddy reflux 0.5h of system, stop heating, be cooled to-5-0 ℃ makes the product crystallization, filtering and washing, filtrate is refluxed after concentrating again, crystallization operation, obtains altogether product white solid 31.2g(yield 98%).
(1) add successively 24g1-(4-benzyloxy-phenyl)-2-propyl group-1-ketone, 24g CuBr in the 1L there-necked flask
2200 mL methylene dichloride and 1,2-ethylene dichloride mixed solution (the two volume ratio is 1:1), the 200mL methyl-formiate, reflux, TLC plate tracking monitor to main raw material (1-(4-benzyloxy-phenyl)-2-propyl group-1-ketone) reacts completely, and stops heating, be cooled to room temperature (25 ℃), reaction finishes to obtain reaction solution.
(2) reaction solution is through the sand core funnel suction filtration, filtrate steams solvent, obtain crude product brown oil 36.7g, add the 230mL ethyl acetate in crude product, the muddy reflux 1h of system, stop heating, be cooled to-15--10 ℃ makes the product crystallization, filtering and washing, filtrate is refluxed after concentrating again, crystallization operation, obtains altogether product white solid 30.3g(yield 95%).
embodiment 3
(1) add successively 24g1-(4-benzyloxy-phenyl)-2-propyl group-1-ketone, 240g CuBr in the 1L there-necked flask
2230 mL methyl-formiates, ethyl formate and methyl acetate mixed solution (three person's volume ratio is 1: 2: 1), 200mL DMF, reflux, TLC plate tracking monitor to main raw material (1-(4-benzyloxy-phenyl)-2-propyl group-1-ketone) reacts completely, stop heating, be cooled to room temperature (25 ℃), reaction finishes to obtain reaction solution.
(2) reaction solution is through the sand core funnel suction filtration, filtrate steams solvent, obtain crude product brown oil 37.0g, add 230mLDMF in crude product, the muddy reflux 2h of system, stop heating, be cooled to-10--5 ℃ makes the product crystallization, filtering and washing, filtrate is refluxed after concentrating again, crystallization operation, obtains altogether product white solid 30.9g(yield 97%).
(1) add successively 24g1-(4-benzyloxy-phenyl)-2-propyl group-1-ketone, 120g CuBr in the 1L there-necked flask
2, 230 mLDME, 200mL NMP, reflux, TLC plate tracking monitor to main raw material (1-(4-benzyloxy-phenyl)-2-propyl group-1-ketone) reacts completely, and stops heating, is cooled to room temperature (25 ℃), and reaction finishes to obtain reaction solution.
(2) reaction solution is through the sand core funnel suction filtration, filtrate steams solvent, obtain crude product brown oil 37.2g, add 230mL ethyl acetate and alcohol mixeding liquid (the two volume ratio is 1: 1) in crude product, the muddy reflux 1.5h of system, stop heating, be cooled to-20--17 ℃ makes the product crystallization, filtering and washing, filtrate is refluxed after concentrating again, crystallization operation, obtains altogether product white solid 30.6g(yield 96%).
To above-described embodiment products obtained therefrom, adopt nuclear magnetic resonance analyser to be analyzed, obtain product
1h-NMR collection of illustrative plates (CDCl
3for solvent), Fig. 1 is products therefrom
1h-NMR collection of illustrative plates (CDCl
3for solvent), hydrogen atom in Fig. 1 is belonged to, the ownership data are
1hNMR (CDCl
3, δ):
1.889 (d, 3H, CH
3), 5.146 (s, 2H, CH
2), 5.232 ~ 5.282 (t, 1H, CHBr), 7.021 ~ 7.044 (dd, 2H, C
6h
5), 7.260 ~ 7.442 (m, 5H, C
6h
5), 8.002 ~ 8.025 (dd, 2H, C
6h
5), in hence one can see that above-described embodiment, products therefrom is bazedoxifene acetate intermediate 1-(4-benzyloxy-phenyl)-2-bromopropyl-1-ketone.
Claims (4)
1. the preparation method of a bazedoxifene acetate intermediate 1-(4-benzyloxy-phenyl)-2-bromopropyl-1-ketone, is characterized in that, comprises the following steps:
(1) 1-(4-benzyloxy-phenyl)-2-propyl group-1-ketone and metal bromate salt are added to reflux in organic solvent, after reaction finishes, the cooling reaction solution that obtains;
(2) the treated liquid crude product that obtains of reaction solution, add reflux 0.5-2h in organic solvent by the liquid crude product, refluxes and finish by processing and obtain product;
Wherein, the mass ratio of described 1-(4-benzyloxy-phenyl)-2-propyl group-1-ketone and metal bromate salt is 1: (1-10).
2. the preparation method of bazedoxifene acetate intermediate 1-(4-benzyloxy-phenyl)-2-bromopropyl-1-ketone as claimed in claim 1, is characterized in that, after refluxing in step (2) and finishing, is cooled to crystallization below 0 ℃, suction filtration and obtains product.
3. the preparation method of bazedoxifene acetate intermediate 1-(4-benzyloxy-phenyl)-2-bromopropyl-1-ketone as claimed in claim 1 or 2, is characterized in that, described metal bromate salt is cupric bromide.
4. the preparation method of a kind of bazedoxifene acetate intermediate 1-(4-benzyloxy-phenyl)-2-bromopropyl-1-ketone as claimed in claim 3, described organic solvent is methylene dichloride, 1, one or more in 2-ethylene dichloride, chloroform, ethanol, ethyl acetate, methyl-formiate, ethyl formate, methyl acetate, DMF, DME, NMP.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105061227A (en) * | 2015-07-27 | 2015-11-18 | 广东先强药业有限公司 | Environment-friendly ritodrine hydrochloride production method |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0872468B1 (en) * | 1997-04-15 | 2001-07-25 | Central Glass Company, Limited | Method for producing 3,3-dichloro-1,1,1-trifluoroacetone |
| CN102260154A (en) * | 2011-06-10 | 2011-11-30 | 南通职业大学 | Preparation method of pharmaceutical intermediate alpha-bromo-p-chloropropiophenone |
-
2013
- 2013-09-24 CN CN201310436798.XA patent/CN103483173A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0872468B1 (en) * | 1997-04-15 | 2001-07-25 | Central Glass Company, Limited | Method for producing 3,3-dichloro-1,1,1-trifluoroacetone |
| CN102260154A (en) * | 2011-06-10 | 2011-11-30 | 南通职业大学 | Preparation method of pharmaceutical intermediate alpha-bromo-p-chloropropiophenone |
Non-Patent Citations (3)
| Title |
|---|
| 彭安顺等: "溴化铜作溴化剂合成3-氯-α-溴-苯基乙基酮", 《化学工程师》 * |
| 胡艾希等: "α-溴- 4-取代苯酮的合成", 《精细化工》 * |
| 胡艾希等: "溴化铜对6-甲氧基-2-酰基萘的选择性溴化反应", 《应用化学》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105061227A (en) * | 2015-07-27 | 2015-11-18 | 广东先强药业有限公司 | Environment-friendly ritodrine hydrochloride production method |
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Application publication date: 20140101 |