CN100551912C - A kind of method for preparing imidapril or its intermediate - Google Patents
A kind of method for preparing imidapril or its intermediate Download PDFInfo
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- CN100551912C CN100551912C CNB2007100386558A CN200710038655A CN100551912C CN 100551912 C CN100551912 C CN 100551912C CN B2007100386558 A CNB2007100386558 A CN B2007100386558A CN 200710038655 A CN200710038655 A CN 200710038655A CN 100551912 C CN100551912 C CN 100551912C
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Abstract
The invention provides a kind of method for preparing imidapril intermediate 2-oxo-imidazole alkane derivatives formula I, the 2-oxo-imidazole alkane-4-carboxylates derivatives II and N-(1 (S)-ethoxy carbonyl-3-the phenyl propyl)-L-L-Ala-N-carboxylic acid anhydride III of (S) configuration reacted promptly.Advantage of the present invention is the reaction conditions gentleness, and speed of response is fast, and the yield height pollutes for a short time, has wide practical use; R wherein
1Be hydrogen atom, basic metal, alkaline earth metal atom, C
1-C
4Alkyl or benzyl; Work as R
1During for hydrogen atom, this product is imidapril.
Description
Technical field:
The present invention is specifically related to chemical pharmacy field.Be specifically related to a kind of method for preparing imidapril or its intermediate.
Background technology:
Imidapril is a kind of long-acting, non-thin basic angiotensin converting enzyme inhibitor (ACEI), is used for the treatment of hypertension, chronic congestive heart failure, Acute Myocardial Infarction clinically, reaches diabetic nephropathy.Its antihypertensive effect is obvious, untoward reaction is little, patient's compliance is good, embodies the superiority that is different from other similar medicine and adrenergic receptor binder preparation as new angiotensin-converting enzyme (ACE) inhibitor, is with a wide range of applications in treating cardiovascular disease.
Wherein * represents unsymmetrical carbon.
Photoactive 2-oxo-imidazole alkane derivatives shown in the formula I, it is the important intermediate of imidapril, the method that provides among the Chinese patent CN1032308C is with (2S) 2-amino-4-phenyl-butyric ester and (4S)-1-methyl-3-[(2R)-2-(P-tosyloxy) propionyl]-2-oxo-imidazole alkane-4-carboxylicesters is a raw material, 80 ℃ of following stirring reactions obtained target product after 24 hours in methyl-sulphoxide and triethylamine system.According to the disclosed method of above-mentioned patent specification, the required reaction times is longer, and energy consumption is big, and raw materials cost is higher, has certain defective in Application in Chemical Engineering.
U.S. Pat 4508727 discloses a kind of method, be with 2-oxo-imidazole alkane-4-carboxylicesters and N-[1 (S)-ethoxy carbonyl-3-phenyl propyl]-condensation under alkaline condition of L-L-Ala obtains compound formula (I), this reacts described optimal reaction temperature and is-40 ℃-0 ℃, condition is harsh, and yield lower (＜50%), application prospect is little aspect industrialization.
Summary of the invention:
Technical problem to be solved by this invention is to overcome above-mentioned weak point, and the imidapril preparation method that a kind of raw materials cost of research and design is low, reaction conditions is gentle has especially improved its intermediates preparation.
The invention provides a kind of method for preparing imidapril important intermediate 2-oxo-imidazole alkane derivatives formula I: the 2-oxo-imidazole alkane-4-carboxylates derivatives II and N-(1 (S)-ethoxy carbonyl-3-the phenyl propyl)-L-L-Ala-N-carboxylic acid anhydride III of (S) configuration are reacted promptly.
The concrete preparation method of Compound I provided by the invention is: Compound I I in organic solvent, alkaline condition down and the compound III direct reaction obtain.
R wherein
1Represent hydrogen atom, alkalies and alkaline earth atom, C
1-C
4Alkyl, benzyl etc. are worked as R
1During for hydrogen atom, this product is imidapril.
Described reaction base comprises: alkalimetal hydride (as sodium hydride etc.); Lower alkoxy alkali metal compound (as sodium ethylate, sodium methylate, sodium isopropylate, potassium isopropoxide, sodium tert-butoxide, potassium tert.-butoxide), aminated compounds (amine, diethylamine, triethylamine) etc.; Mineral alkali such as sodium bicarbonate, saleratus, yellow soda ash, salt of wormwood, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, hydrated barta etc.; Be preferably sodium hydride, sodium methylate, potassium tert.-butoxide, sodium isopropylate.Compound (II) is 1: 1～5.0 with the mol ratio of alkali, be preferably 1: 1.5～and 2.5;
Described reaction solvent is: tetrahydrofuran (THF), dioxane, methylene dichloride, DMF, DMSO, (replacement) benzene etc., preferred tetrahydrofuran (THF), dioxane.The consumption of solvent is that every 1g compound (II) uses solvent 5～20mL, preferred 7～12mL.
The mol ratio of Compound I I and compound III is 1: 0.9～1.5 in the described reaction, be preferably 1: 1.05～and 1.2.
Described reaction optimal temperature is-20 ℃～50 ℃, preferred-5 ℃～25 ℃.
According to the inventive method, can prepare racemization and other configuration of compound (I), but must adopt the raw material of respective configuration.
The method for preparing compound formula (I) imidapril intermediate 2-oxo-imidazole alkane derivatives provided by the invention has the reaction conditions gentleness, and easy and simple to handle, speed of response is fast, and the yield height pollutes characteristics such as little, and tangible environmental protection and cost advantage are arranged.
Specific implementation method:
In order to prove absolutely preparation method of the present invention, limiting the scope of the invention should not explained or be interpreted as to following examples only for illustrating and the special case representative.
Embodiment 1
3.5 gram (4S)-1-methyl-2-oxo-imidazole alkane-4-carboxylic acid tert-butyl esters and 40 milliliters of tetrahydrofuran (THF)s are joined in 250 milliliters of three mouthfuls of round-bottomed flasks, ice bath stirs and is cooled to below 0 ℃, adds 2.1 gram sodium hydride pressed powders (active constituent content 60%) in 5 minutes.Low temperature reacted 20 minutes down, added 5.6 gram N-(1 (S)-ethoxy carbonyl-3-phenyl propyl)-L-L-Ala-N-carboxylic acid anhydride pressed powders again in 10 minutes, and low-temp reaction 30 minutes is warmed up to 20 ℃ of reactions 5 hours.Reaction finishes, and obtains 6.8 gram colourless pulpous state (4S)-1-methyl-3{ (2S)-2-[N-[(1S)-1-ethoxycarbonyl-3-hydrocinnamyl through aftertreatment] amino] propionyl }-2-oxo-imidazole alkane-4-carboxylic acid tert-butyl ester.The HPLC detection level is 99.63%, yield 87.2%.
Embodiment 2
3.8 gram (4S)-1-methyl-2-oxo-imidazole alkane-4-carboxylic acid tert-butyl esters and 45 milliliters of tetrahydrofuran (THF)s are joined in 250 milliliters of three mouthfuls of round-bottomed flasks, and ice bath stirs and is cooled to below 0 ℃, adds 3.0 gram sodium methylate pressed powders in 5 minutes.Low temperature reacted 20 minutes down, added 6.1 gram N-(1 (S)-ethoxy carbonyl-3-phenyl propyl)-L-L-Ala-N-carboxylic acid anhydride pressed powders again in 10 minutes, and low-temp reaction 30 minutes is warmed up to 20 ℃ of reactions 5 hours.Reaction finishes, and obtains 7.3 gram colourless pulpous state (4S)-1-methyl-3{ (2S)-2-[N-[(1S)-1-ethoxycarbonyl-3-hydrocinnamyl through aftertreatment] amino] propionyl }-2-oxo-imidazole alkane-4-carboxylic acid tert-butyl ester.The HPLC detection level is 99.42%, yield 86.1%.
Embodiment 3
3.2 gram (4S)-1-methyl-2-oxo-imidazole alkane-4-carboxylic acid tert-butyl esters and 35 milliliters of tetrahydrofuran (THF)s are joined in 250 milliliters of three mouthfuls of round-bottomed flasks, and ice bath stirs and is cooled to below 0 ℃, adds 4.0 gram sodium isopropylate pressed powders in 5 minutes.Low temperature reacted 20 minutes down, added 5.1 gram N-(1 (S)-ethoxy carbonyl-3-phenyl propyl)-L-L-Ala-N-carboxylic acid anhydride pressed powders again in 10 minutes, and low-temp reaction 30 minutes is warmed up to 20 ℃ of reactions 5 hours.Reaction finishes, and obtains 6.1 gram colourless pulpous state (4S)-1-methyl-3{ (2S)-2-[N-[(1S)-1-ethoxycarbonyl-3-hydrocinnamyl through aftertreatment] amino] propionyl }-2-oxo-imidazole alkane-4-carboxylic acid tert-butyl ester.The HPLC detection level is 99.25%, yield 85.7%.
Embodiment 4
3.9 gram (4S)-1-methyl-2-oxo-imidazole alkane-4-carboxylic acid tert-butyl esters and 45 milliliters of tetrahydrofuran (THF)s are joined in 250 milliliters of three mouthfuls of round-bottomed flasks, and ice bath stirs and is cooled to below 0 ℃, adds 6.5 gram potassium tert.-butoxide pressed powders in 5 minutes.Low temperature reacted 20 minutes down, added 6.2 gram N-(1 (S)-ethoxy carbonyl-3-phenyl propyl)-L-L-Ala-N-carboxylic acid anhydride pressed powders again in 10 minutes, and low-temp reaction 30 minutes is warmed up to 20 ℃ of reactions 5 hours.Reaction finishes, and obtains 7.6 gram colourless pulpous state (4S)-1-methyl-3{ (2S)-2-[N-[(1S)-1-ethoxycarbonyl-3-hydrocinnamyl through aftertreatment] amino] propionyl }-2-oxo-imidazole alkane-4-carboxylic acid tert-butyl ester.The HPLC detection level is 99.32%, yield 87.4%.
Embodiment 5
4.2 gram (4S)-1-methyl-2-oxo-imidazole alkane-4-carboxylic acid tert-butyl esters and 50 milliliters of tetrahydrofuran (THF)s are joined in 250 milliliters of three mouthfuls of round-bottomed flasks, and ice bath stirs and is cooled to below 0 ℃, adds 2.5 gram sodium hydrate solids in 5 minutes.Low temperature reacted 20 minutes down, added 6.7 gram N-(1 (S)-ethoxy carbonyl-3-phenyl propyl)-L-L-Ala-N-carboxylic acid anhydride pressed powders again in 10 minutes, and low-temp reaction 30 minutes is warmed up to 20 ℃ of reactions 5 hours.Reaction finishes, and obtains 8.1 gram colourless pulpous state (4S)-1-methyl-3{ (2S)-2-[N-[(1S)-1-ethoxycarbonyl-3-hydrocinnamyl through aftertreatment] amino] propionyl }-2-oxo-imidazole alkane-4-carboxylic acid tert-butyl ester.The HPLC detection level is 99.34%, yield 86.4%.
Embodiment 6
3.4 gram (4S)-1-methyl-2-oxo-imidazole alkane-4-carboxylic acid tert-butyl esters and 40 milliliters of tetrahydrofuran (THF)s are joined in 250 milliliters of three mouthfuls of round-bottomed flasks, and ice bath stirs and is cooled to below 0 ℃, adds 3.5 gram potash solid powder in 5 minutes.Low temperature reacted 20 minutes down, added 5.5 gram N-(1 (S)-ethoxy carbonyl-3-phenyl propyl)-L-L-Ala-N-carboxylic acid anhydride pressed powders again in 10 minutes, and low-temp reaction 30 minutes is warmed up to 20 ℃ of reactions 5 hours.Reaction finishes, and obtains 6.4 gram colourless pulpous state (4S)-1-methyl-3{ (2S)-2-[N-[(1S)-1-ethoxycarbonyl-3-hydrocinnamyl through aftertreatment] amino] propionyl }-2-oxo-imidazole alkane-4-carboxylic acid tert-butyl ester.The HPLC detection level is 99.37%, yield 84.2%.
Embodiment 7
3.7 gram (4S)-1-methyl-2-oxo-imidazole alkane-4-carboxylic acid tert-butyl esters and 45 milliliters of dioxane are joined in 250 milliliters of three mouthfuls of round-bottomed flasks, ice bath stirs and is cooled to below 0 ℃, adds 2.2 gram sodium hydride pressed powders (active constituent content 60%) in 5 minutes.Low temperature reacted 20 minutes down, added 5.9 gram N-(1 (S)-ethoxy carbonyl-3-phenyl propyl)-L-L-Ala-N-carboxylic acid anhydride pressed powders again in 10 minutes, and low-temp reaction 30 minutes is warmed up to 20 ℃ of reactions 5 hours.Reaction finishes, and obtains 7.3 gram colourless pulpous state (4S)-1-methyl-3{ (2S)-2-[N-[(1S)-1-ethoxycarbonyl-3-hydrocinnamyl through aftertreatment] amino] propionyl }-2-oxo-imidazole alkane-4-carboxylic acid tert-butyl ester.The HPLC detection level is 99.45%, yield 88.7%.
Embodiment 8
With 3.3 gram (4S)-1-methyl-2-oxo-imidazole alkane-4-carboxylic acid tert-butyl ester and 40 milliliters of N, dinethylformamide is added in 250 milliliters of three mouthfuls of round-bottomed flasks, ice bath stirs and is cooled to below 0 ℃, adds 2.0 gram sodium hydride pressed powders (active constituent content 60%) in 5 minutes.Low temperature reacted 20 minutes down, added 5.3 gram N-(1 (S)-ethoxy carbonyl-3-phenyl propyl)-L-L-Ala-N-carboxylic acid anhydride pressed powders again in 10 minutes, and low-temp reaction 30 minutes is warmed up to 20 ℃ of reactions 5 hours.Reaction finishes, and obtains 6.4 gram colourless pulpous state (4S)-1-methyl-3{ (2S)-2-[N-[(1S)-1-ethoxycarbonyl-3-hydrocinnamyl through aftertreatment] amino] propionyl }-2-oxo-imidazole alkane-4-carboxylic acid tert-butyl ester.The HPLC detection level is 99.27%, yield 87.3%.
Embodiment 9
4.5 gram (4S)-1-methyl-2-oxo-imidazole alkane-4-benzyl carboxylates and 50 milliliters of tetrahydrofuran (THF)s are joined in 250 milliliters of three mouthfuls of round-bottomed flasks, ice bath stirs and is cooled to below 0 ℃, adds 2.4 gram sodium hydride pressed powders (active constituent content 60%) in 5 minutes.Low temperature reacted 20 minutes down, added 6.4 gram N-(1 (S)-ethoxy carbonyl-3-phenyl propyl)-L-L-Ala-N-carboxylic acid anhydride pressed powders again in 10 minutes, and low-temp reaction 30 minutes is warmed up to 20 ℃ of reactions 5 hours.Reaction finishes, and obtains 8.2 gram colourless pulpous state (4S)-1-methyl-3{ (2S)-2-[N-[(1S)-1-ethoxycarbonyl-3-hydrocinnamyl through aftertreatment] amino] propionyl }-2-oxo-imidazole alkane-4-benzyl carboxylate.The HPLC detection level is 99.48%, yield 85.6%.
Embodiment 10
3.6 gram (4S)-1-methyl-2-oxo-imidazole alkane-4-carboxylate methyl esters and 50 milliliters of tetrahydrofuran (THF)s are joined in 250 milliliters of three mouthfuls of round-bottomed flasks, and ice bath stirs and is cooled to below 0 ℃, adds 2.5 gram calcium hydroxide solids in 5 minutes.Low temperature reacted 20 minutes down, added 7.3 gram N-(1 (S)-ethoxy carbonyl-3-phenyl propyl)-L-L-Ala-N-carboxylic acid anhydride pressed powders again in 10 minutes, and low-temp reaction 30 minutes is warmed up to 20 ℃ of reactions 5 hours.Reaction finishes, and obtains 8.0 gram colourless pulpous state (4S)-1-methyl-3{ (2S)-2-[N-[(1S)-1-ethoxycarbonyl-3-hydrocinnamyl through aftertreatment] amino] propionyl }-2-oxo-imidazole alkane-4-carboxylate methyl ester.The HPLC detection level is 99.31%, yield 86.3%.
Embodiment 11
3.5 gram (4S)-1-methyl-2-oxo-imidazole alkane-4-carboxylic acid, ethyl esters and 50 milliliters of tetrahydrofuran (THF)s are joined in 250 milliliters of three mouthfuls of round-bottomed flasks, and ice bath stirs and is cooled to below 0 ℃, adds 5.5 gram hydrated barta solids in 5 minutes.Low temperature reacted 20 minutes down, added 6.5 gram N-(1 (S)-ethoxy carbonyl-3-phenyl propyl)-L-L-Ala-N-carboxylic acid anhydride pressed powders again in 10 minutes, and low-temp reaction 30 minutes is warmed up to 20 ℃ of reactions 5 hours.Reaction finishes, and obtains 7.3 gram colourless pulpous state (4S)-1-methyl-3{ (2S)-2-[N-[(1S)-1-ethoxycarbonyl-3-hydrocinnamyl through aftertreatment] amino] propionyl }-2-oxo-imidazole alkane-4-carboxylic acid, ethyl ester.The HPLC detection level is 99.42%, yield 85.6%.
Embodiment 12
4.1 gram (4S)-1-methyl-2-oxo-imidazole alkane-4-carboxylic acids and 50 milliliters of tetrahydrofuran (THF)s are joined in 250 milliliters of three mouthfuls of round-bottomed flasks, and ice bath stirs and is cooled to below 0 ℃, adds 3.5 gram sodium hydrate solids in 5 minutes.Low temperature reacted 20 minutes down, added 9.1 gram N-(1 (S)-ethoxy carbonyl-3-phenyl propyl)-L-L-Ala-N-carboxylic acid anhydride pressed powders again in 10 minutes, and low-temp reaction 30 minutes is warmed up to 20 ℃ of reactions 5 hours.Reaction finishes, and obtains 9.5 gram colourless pulpous state (4S)-1-methyl-3{ (2S)-2-[N-[(1S)-1-ethoxycarbonyl-3-hydrocinnamyl through aftertreatment] amino] propionyl }-2-oxo-imidazole alkane-4-carboxylic acid (imidapril).The HPLC detection level is 99.36%, yield 85.6%.
Claims (13)
1. the method for a preparation I compound, it is characterized in that formula II (4S)-1-methyl-2-oxo-imidazole alkane-4-carboxylicesters and formula III N-(1 (S)-ethoxy carbonyl-3-phenyl propyl)-L-L-Ala-N-carboxylic acid anhydride is in organic solvent, under alkaline condition, direct reaction promptly gets Compound I:
R wherein
1Be hydrogen atom, basic metal, alkaline earth metal atom, C
1-C
4Alkyl or benzyl.
2. the method for a kind of preparation I compound according to claim 1 is characterized in that the mol ratio of Compound I I and compound III is 1: 0.9～1.5 in the described reaction.
3. the method for a kind of preparation I compound according to claim 1 is characterized in that the mol ratio of Compound I I and compound III is 1: 1.05～1.2 in the described reaction.
4. the method for a kind of preparation I compound according to claim 1 is characterized in that described alkali is sodium hydride, sodium ethylate, sodium methylate, sodium isopropylate, potassium isopropoxide, sodium tert-butoxide, potassium tert.-butoxide, diethylamine, triethylamine, sodium bicarbonate, saleratus, yellow soda ash, salt of wormwood, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide or hydrated barta.
5. the method for a kind of preparation I compound according to claim 1 is characterized in that described alkali is sodium hydride, sodium methylate, potassium tert.-butoxide or sodium isopropylate.
6. according to the method for claim 4, the consumption that it is characterized in that described alkali is that the mol ratio of Compound I I and alkali is 1: 1～5.0.
7. according to the method for claim 4, the consumption that it is characterized in that described alkali is that the mol ratio of Compound I I and alkali is 1: 1.5～2.5.
8. the method for a kind of preparation I compound according to claim 1 is characterized in that described organic solvent is tetrahydrofuran (THF), dioxane, methylene dichloride, DMF or DMSO.
9. the method for a kind of preparation I compound according to claim 1 is characterized in that described organic solvent is tetrahydrofuran (THF) or dioxane.
10. according to Claim 8 or 9 method, the consumption that it is characterized in that solvent is that every 1g Compound I I uses solvent 5～20mL.
11. according to Claim 8 or 9 method, the consumption that it is characterized in that solvent is that every 1g Compound I I uses solvent 7～12mL.
12. the method for a kind of preparation I compound according to claim 1 is characterized in that this temperature of reaction is-20 ℃～50 ℃.
13. the method for a kind of preparation I compound according to claim 1 is characterized in that this temperature of reaction is-5 ℃～25 ℃.
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| KR100915174B1 (en) * | 2007-09-07 | 2009-09-03 | 네오코리아(주) | Process for preparing new 2-oxoimidazolidine derivate |
| CN104119424B (en) * | 2014-07-01 | 2018-12-18 | 上海天慈生物谷生物工程有限公司 | The preparation method of (4S) -3- [(2S) -2 [(1S) -1- ethoxycarbonyl-3-phenylpropyl] aminopropionyl] -1- methyl -2- oxoimidazolinium -4- carboxylic acid |
| CN105713068B (en) * | 2014-12-04 | 2021-04-20 | 湖南九典制药股份有限公司 | Method for preparing imidapril key intermediate and derivative thereof |
| CN111253315A (en) * | 2020-03-10 | 2020-06-09 | 北京阳光诺和药物研究有限公司 | Imidapril hydrochloride organic impurity and preparation method thereof |
| CN113024632B (en) * | 2021-03-28 | 2023-03-28 | 山东中健康桥制药有限公司 | Preparation method of imidapril hydrochloride |
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Non-Patent Citations (2)
| Title |
|---|
| Studies on angiotensin converting enzyme inhibitors. 4.Synthesis and angiotensin converting enzyme inhibitoryactivities of 3-acyl-1-alkyl-2-oxoimidazolidine-4-carboxylic acidderivatives. Kimiaki Hayashi, et al.J Med Chem,Vol.32 No.2. 1989 |
| Studies on angiotensin converting enzyme inhibitors. 4.Synthesis and angiotensin converting enzyme inhibitoryactivities of 3-acyl-1-alkyl-2-oxoimidazolidine-4-carboxylic acidderivatives. Kimiaki Hayashi, et al.J Med Chem,Vol.32 No.2. 1989 * |
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