CN101362730A - Method for preparing losartan side chain compound - Google Patents
Method for preparing losartan side chain compound Download PDFInfo
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- CN101362730A CN101362730A CNA2008102229861A CN200810222986A CN101362730A CN 101362730 A CN101362730 A CN 101362730A CN A2008102229861 A CNA2008102229861 A CN A2008102229861A CN 200810222986 A CN200810222986 A CN 200810222986A CN 101362730 A CN101362730 A CN 101362730A
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Abstract
The invention relates to a method for preparing valsartan side-chain compounds, which comprises the steps as follows: the compounds of Structural Formula II or/and the compounds of Structural Formula III are dissolved in an organic solvent for hydrogen reduction under the function of a catalyst and at the temperature of 20 DEG C to 100 DEG C; the organic solvent is chosen from alcohol of C1 to C4, tetrahydrofuran and ethyl acetate; the catalyst is chosen from palladium carbon and Raney nickel.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, relate to the preparation method of husky smooth hypotensor important intermediate losartan side chain compound.
Background technology
The structural formula II compound is the husky smooth hypotensor important intermediate losartan side chain compound of preparation.Usually, the structural formula II compound all obtains by structural formula I compound bromination, and bromide reagent commonly used has bromine, NBS, and on behalf of patent, C5H6Br2N2O2s etc. EP470794 is arranged, EP0470795, US5310928, EP1777224, WO2006067215.
No matter take the sort of bromide reagent, all have the problem of excessive bromination, can have a certain amount of dibromo compound (structural formula II I compounds) in the product.When we pass through the crystalline mode, when obtaining target product, often contain a small amount of raw material (structural formula I compounds) in the crystalline mother solution, a large amount of monobromide (structural formula II compounds), a part of dibromo compound (structural formula II I compounds).
In view of this type of biphenol compound all obtains (EP470794, EP0470795, US5310928, EP1777224, WO20060672150) severe reaction conditions, employed raw material and catalyzer costliness by Grignard reagent or phenylo boric acid and aryl bromide coupling.Therefore, the bromination crystalline mother solution of I compounds is reclaimed,, still, positive meaning is arranged all from the angle of environmental protection not only from economic angle.
The inventor has found a bromination crystalline mother solution recovery structure formula I compounds method from structural formula I compounds through experimental study, and this method has simple to operate, the segregative characteristics of product, present method
Can be used as a kind of method, be used for reclaiming raw material from the bromination mother liquor of above compound.
Summary of the invention
The invention provides a kind of preparation method of formula I compound, the reaction formula of this method is as follows:
Wherein
Formula I compound also is the husky smooth hypotensor important intermediate of preparation.
Preparation method of the present invention comprises structural formula II or structure III compound (can be the mixture of single bromine compounds or monobromo or dibromo compound) are dissolved in organic solvent, carries out hydrogen reducing and obtain structural formula I compound under the effect of catalyzer.
Wherein said organic solvent is selected from the alcohol of C1-C4, tetrahydrofuran (THF), ethyl acetate, preferred alcohol.
Catalyzer is selected from palladium carbon, Raney Ni, preferred palladium carbon.
The amount of catalyzer is the 1%-20% of reactant weight, and is wherein preferred 5%.
Temperature of reaction between 20-100 ℃, wherein preferred 25 ℃.
Reaction times 24-60 hour, wherein preferred 24 hours.
The preparation method of formula I compound of the present invention, except that being used to prepare the husky smooth hypotensor side chain formula I compound, also can be used for from containing a small amount of structural formula I compound, a large amount of structural formula II compounds reclaims preparation structural formula I compound in the formula I bromination reaction crystalline mother solution of a part of structural formula II I compound.
As long as the present invention will contain a small amount of structural formula I compound as the application of reclaiming raw material the time, a large amount of structural formula II compounds, be dissolved in the organic solvent described in the above-mentioned reaction formula behind the crystalline mother solution evaporate to dryness behind the bromination reaction of part structural formula II I compound, under the effect of catalyzer, carry out the product that hydrogen reducing can obtain containing structural formula I compound, with this product carry out purifying get final product structural formula I compound, use as the husky smooth hypotensor important intermediate of preparation.
Preparation method's safety of the present invention, economy, environmental protection, simple to operate, product is easily separated, and it is valuable being used in and reclaiming raw material from the bromination mother liquor of above compound.
Embodiment
Following example should not be considered as it restriction to this patent just for the present invention is described
Synthesizing of embodiment 1:5-[2-(4 '-methyl diphenyl)]-2-H-imidazoles
In the 250ml there-necked flask, add 25.2g (010mol) 5-[2-(4 '-bromomethylbiphenyl)]-2-H-imidazoles, the 70ml tetrahydrofuran (THF), 0.7g palladium carbon stirred 30 minutes, use the nitrogen replacement air, feed hydrogen then, reaction is 24 hours under the room temperature, and reaction finishes, processing obtains 5-[2-(4 '-methyl diphenyl)]-2-H-imidazoles, yield 84%.
1HNMR(CDCl3)：2.25(s，3H)，6.95(d，2H)，7.10(d，2H)，7.50-7.70(m，4H)
Synthesizing of embodiment 2:5-[2-(4 '-methyl diphenyl)]-2-H-imidazoles
Other condition is constant, and solvent is changed to ethyl acetate by ethanol, yield 70%
Synthesizing of embodiment 3:5-[2-(4 '-methyl diphenyl)]-2-trityl group-imidazoles
In the 250ml there-necked flask, add 49.5g (010mol) 5-[2-(4 '-bromomethylbiphenyl)]-2-H-imidazoles, the 210ml tetrahydrofuran (THF), 0.7g palladium carbon stirred 30 minutes, use the nitrogen replacement air, feed hydrogen then, reaction is 24 hours under the room temperature, and reaction finishes, processing obtains 5-[2-(4 '-methyl diphenyl)]-2-trityl group-imidazoles, yield 70%.
1HNMR(CDCl3)：2.25(s，3H)，6.90-7.00(m，10H)，7.20-7.45(m，12H)，7.85-7.90(m，1H)
Synthesizing of embodiment 4:5-[2-(4 '-methyl diphenyl)]-2-trityl group-imidazoles
In the 250ml there-necked flask, add 25.2g 5-[2-(4 '-bromomethylbiphenyl)]-2-trityl group-imidazoles (HPLC content 80%) and 5-[2-(4 '-two bromomethylbiphenyls)]-2-trityl group imidazoles (HPLC content 20%) mixture, 70ml methyl alcohol, 1g palladium carbon stirred 30 minutes, use the nitrogen replacement air, feed hydrogen then, reaction is 30 hours under the room temperature, and reaction finishes, processing obtains 5-[2-(4 '-methyl diphenyl)]-2-trityl group-imidazoles, yield 50%.
Embodiment 5: implement synthetic (recovery of bromination mother liquor) of 5-[2-(4 '-methyl diphenyl)]-2-trityl group-imidazoles
In the 250ml there-necked flask, add 25.2g 5-[2-(4 '-methyl diphenyl)]-2-trityl group-imidazoles bromination recovery mother liquor evaporate to dryness resistates and (comprise 5-[2-(4 '-bromomethylbiphenyl)]-2-trityl group-imidazoles (HPLC content 75%), 5-[2-(4 '-two bromomethylbiphenyls)]-2-trityl group imidazoles (HPLC content 20%), 5-[2-(4 '-methyl diphenyl)]-2-trityl group imidazoles (HPLC content 4%)) is dissolved in the 70ml methyl alcohol, add 1g palladium carbon, stirred 30 minutes, use the nitrogen replacement air, feed hydrogen then, reaction is 30 hours under the room temperature, reaction finishes, processing obtains 5-[2-(4 '-methyl diphenyl)]-2-trityl group-imidazoles, yield 48%.
Embodiment 6: implement synthetic (recovery of bromination mother liquor) of 5-[2-(4 '-methyl diphenyl)]-2-H-imidazoles
In the 250ml there-necked flask, add 30g 5-[2-(4 '-methyl diphenyl)]-2-H-imidazoles bromination crystalline mother solution evaporate to dryness resistates and (comprise 5-[2-(4 '-bromomethylbiphenyl)]-2-H-imidazoles (HPLC content 60%), 5-[2-(4 '-two bromomethylbiphenyls)]-2-H-imidazoles (HPLC content 20%), 5-[2-(4 '-methyl diphenyl)]-2-H-imidazoles (HPLC content 4%)) is dissolved in the 70ml ethanol, add 0.8g palladium carbon, stirred 30 minutes, use the nitrogen replacement air, feed hydrogen then, reaction is 30 hours under the room temperature, reaction finishes, and handles to obtain 5-[2-(4 '-methyl diphenyl)]-2-trityl group-imidazoles, yield 34%.
Claims (10)
1, a kind of preparation method of formula I compound is characterized in that, may further comprise the steps:
Wherein
Structural formula II or/and the structure III compound is dissolved in organic solvent, under the effect of catalyzer, under 20-100 ℃ of temperature, is carried out hydrogen reducing, and described organic solvent is selected from the alcohol of C1-C4, tetrahydrofuran (THF), ethyl acetate; Described catalyzer is selected from palladium carbon, Raney Ni.
2. according to the preparation method of claim 1, it is characterized in that described organic solvent is an ethanol.
3. according to the preparation method of claim 1, it is characterized in that described catalyzer is a palladium carbon.
4. according to the preparation method of claim 1, it is characterized in that the amount of described catalyzer is the 1%-20% of reactant weight.
5. according to the preparation method of claim 1, it is characterized in that the amount of described catalyzer is 5% of a reactant weight.
6. according to the preparation method of claim 1, it is characterized in that temperature of reaction is 25 ℃.
7. according to the preparation method of claim 1, it is characterized in that the reaction times is 24-60 hour.
8. according to the preparation method of claim 1, it is characterized in that the reaction times is 24 hours.
9. according to the preparation method of claim 1, it is characterized in that, from structural formula I compound bromination reaction post crystallization mother liquor, reclaim preparation structural formula I compound.Crystalline mother solution is characterised in that and contains a small amount of structural formula I compound, a large amount of structural formula II compounds, a part of structural formula II I compound.
10. according to the preparation method of claim 1, it is characterized in that, step is as follows: will (contain structural formula I compound, the structural formula II compound, structural formula II I compound) resistates is dissolved in the organic solvent behind the formula I compound bromination reaction crystalline mother solution evaporate to dryness, under the effect of catalyzer, carry out hydrogen reducing, obtain containing the product of structural formula I compound, this product is carried out purifying promptly get structural formula I compound.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101735106B (en) * | 2009-12-22 | 2013-12-25 | 华润赛科药业有限责任公司 | Method for preparing biphenyl compound |
| CN104072408A (en) * | 2010-03-12 | 2014-10-01 | 日本曹达株式会社 | Compound containing pyridine ring and method for producing halogenated picoline derivative and tetrazolyloxime derivative |
| CN114478315A (en) * | 2022-02-25 | 2022-05-13 | 山东艾孚特科技有限公司 | Method for catalytic reduction of bromosartanbiphenyl waste residue by halogen modified Pd/C catalyst |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| GB9017480D0 (en) * | 1990-08-09 | 1990-09-26 | Ici Plc | Chemical process |
| US5892094A (en) * | 1997-01-08 | 1999-04-06 | Sumika Fine Chemicals Co., Ltd. | Process for preparing 4'-methyl-2-cyanobiphenyl |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101735106B (en) * | 2009-12-22 | 2013-12-25 | 华润赛科药业有限责任公司 | Method for preparing biphenyl compound |
| CN104072408A (en) * | 2010-03-12 | 2014-10-01 | 日本曹达株式会社 | Compound containing pyridine ring and method for producing halogenated picoline derivative and tetrazolyloxime derivative |
| CN104072408B (en) * | 2010-03-12 | 2016-09-14 | 日本曹达株式会社 | Compound containing pyridine ring and halogenated methyl pyridine derivate and the manufacture method of tetrazole radical 9 oxime derivate |
| CN114478315A (en) * | 2022-02-25 | 2022-05-13 | 山东艾孚特科技有限公司 | Method for catalytic reduction of bromosartanbiphenyl waste residue by halogen modified Pd/C catalyst |
| CN114478315B (en) * | 2022-02-25 | 2023-10-31 | 山东艾孚特科技有限公司 | Method for catalytic reduction of irosartan biphenyl waste residues by using halogen-modified Pd/C catalyst |
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Address after: 100021 Beijing city Chaoyang District Jinsong three District No. 302 Huateng building room 1101 Patentee after: China Resources Saike Pharmaceutical Co., Ltd. Address before: 100021 Beijing city Chaoyang District Jinsong three District No. 302 Huateng building room 1101 Patentee before: Saike Pharmaceutical Co., Ltd., Beijing |