CN101302218B - Preparation of Trandolapril diketone - Google Patents
Preparation of Trandolapril diketone Download PDFInfo
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- CN101302218B CN101302218B CN2007100404217A CN200710040421A CN101302218B CN 101302218 B CN101302218 B CN 101302218B CN 2007100404217 A CN2007100404217 A CN 2007100404217A CN 200710040421 A CN200710040421 A CN 200710040421A CN 101302218 B CN101302218 B CN 101302218B
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- Prior art keywords
- trandolapril
- diketone
- preparation
- organic solvent
- trolapril
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- VXFJYXUZANRPDJ-UTUSYQKASA-N CCOC([C@H](CCc1ccccc1)N[C@@H](C)C(N([C@@H](C1)C(O)=O)C2[C@@H]1CCCC2)=O)=O Chemical compound CCOC([C@H](CCc1ccccc1)N[C@@H](C)C(N([C@@H](C1)C(O)=O)C2[C@@H]1CCCC2)=O)=O VXFJYXUZANRPDJ-UTUSYQKASA-N 0.000 description 1
- 0 CCON(C1)C1(CCc1ccccc1)N([C@@](*)C(N([C@]1C2)[C@@]3C2CCCC3)=O)C1=O Chemical compound CCON(C1)C1(CCc1ccccc1)N([C@@](*)C(N([C@]1C2)[C@@]3C2CCCC3)=O)C1=O 0.000 description 1
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- Indole Compounds (AREA)
Abstract
The invention discloses a method for preparing Trandolapril diketone. The method comprises a step of using Trandolapril to react in a soluble organic solvent, wherein the reaction temperature is lower than or equal to the boiling point of the organic solvent, and then the Trandolapril diketone can be obtained. The method is simple and easy to operate and high in yield, and greatly reduces the three wastes.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, specifically, relate to the preparation method of Trandolapril diketone.
Background technology
Trolapril (Trandolapril) is by the exploitation of the Roussel Uclaf company of Germany (II), a kind of long lasting angiotensin-convertion enzyme inhibitor (ACEI) that the Sanofi-Aventis company of France produces, went on the market in France in 1993, be used for the treatment of hypertension, congestive heart failure and myocardial infarction.Its chemical being called (2S, 3aR, 7aS)-1-[(2S)-2-[[(1S)-and 1-(ethoxycarbonyl)-3-hydrocinnamyl] amino]-the 1-oxopropyl] octahydro-1H-Indoline-2-carboxylic acid.
Trandolapril diketone (I) is the impurity of Trolapril (II), and about requiring the amount of control Trandolapril diketone (I) to be no more than 0.5% in the record of Trolapril, the existence of Trandolapril diketone can influence the physiologically active of Trolapril in the European Pharmacopoeias in 2006.
For synthetic qualified Trolapril, need at first synthetic Trandolapril diketone in contrast, with the limit of control Trandolapril diketone.
Document is not seen the preparation report of this Trandolapril diketone.
Document (Journal of Medicinal Chemistry, 30 (6), 992-8; 1987) reported the preparation method of Trandolapril diketone optical isomer in:
(2S, 3aS, 7aS)-1-[(2S)-2-[[(1S)-and 1-(ethoxycarbonyl)-3-hydrocinnamyl] amino]-the 1-oxopropyl] octahydro-1H-Indoline-2-carboxylic acid (Trolapril optical isomer) is at I-hydroxybenzotriazole and DCC (N, N '-dicyclohexylcarbodiimide) effect down, room temperature reaction 24 hours, obtain ethyl-(2S)-2-[(3S, 5aS, 9aS, 10aS)-the 3-methyl isophthalic acid, 4-dioxo decahydro pyrazine is [1,2-a] indoles-2 (1H)-yl also]-4-phenylbutyric acid (Trandolapril diketone optical isomer).This method is used DCC, and it is more to produce the three wastes, and by product DCU of generation (N, N '-dicyclohexyl urea) and I-hydroxybenzotriazole all need reclaim, complex operation, yield only 47%.
Summary of the invention
For solving the technical problem that does not have well to prepare the method for Trandolapril diketone in the prior art, the present inventor utilizes the characteristics of Trolapril self, with it is raw material, organic solvent with the solubilized Trolapril is a solvent, react certain hour being less than or equal under the boiling temperature of this organic solvent, obtain Trandolapril diketone.
Therefore, the invention provides a kind of preparation method of Trandolapril diketone, comprise Trolapril is reacted in soluble organic solvent, wherein temperature of reaction is less than or equal to the boiling point of this organic solvent, promptly gets Trandolapril diketone.
Described organic solvent is toluene, benzene, methylene dichloride, chloroform or ethyl acetate, preferred toluene.
Temperature of reaction is preferably 70～110 ℃.
Reaction times is preferably 1～24 hour.
With respect to prior art, the advantage of the inventive method is as follows:
1. operation steps is simple;
2. yield is higher;
3. do not use DCC, reduce the three wastes, the protection environment.
Embodiment
Embodiment 1
(2S, 3aR, 7aS)-1-[(2S)-2-[[(1S)-and 1-(ethoxycarbonyl)-3-hydrocinnamyl] amino]-the 1-oxopropyl] octahydro-1H-Indoline-2-carboxylic acid (Trolapril) (10g, add toluene 20ml 23mmol), 110 ℃ of following backflow 7h, evaporated under reduced pressure gets white solid 9.1g, yield: 95%, and 142～144 ℃ of fusing points.MS(m/z)：435(M+Na)
+；847(2M+Na)
+。
Embodiment 2
(2S, 3aR, 7aS)-1-[(2S)-2-[[(1S)-and 1-(ethoxycarbonyl)-3-hydrocinnamyl] amino]-the 1-oxopropyl] octahydro-1H-Indoline-2-carboxylic acid (Trolapril) (1g, 2.3mmol) the middle ethyl acetate 20ml that adds, 77 ℃ are reacted 12h down, cross post and get white solid 0.69g, yield: 72%, 142～144 ℃ of fusing points.MS(m/z)：435(M+Na)
+；847(2M+Na)
+。
Embodiment 3
(2S, 3aR, 7aS)-1-[(2S)-2-[[(1S)-and 1-(ethoxycarbonyl)-3-hydrocinnamyl] amino]-the 1-oxopropyl] octahydro-1H-Indoline-2-carboxylic acid (Trolapril) (2g, 4.6mmol) the middle methylene dichloride 20ml that adds, 40 ℃ are reacted 22h down, cross post and get white solid 0.76g, yield: 40%, 142～144 ℃ of fusing points.MS(m/z)：435(M+Na)
+；847(2M+Na)
+。
Embodiment 4
(2S, 3aR, 7aS)-1-[(2S)-2-[[(1S)-and 1-(ethoxycarbonyl)-3-hydrocinnamyl] amino]-the 1-oxopropyl] octahydro-1H-Indoline-2-carboxylic acid (Trolapril) (2g, 4.6mmol) the middle benzene 20ml that adds, 80 ℃ of following backflow 10h, cross post and get white solid 1.5g, yield: 79%, 142～143 ℃ of fusing points.MS(m/z)：435(M+Na)
+；847(2M+Na)
+。
Embodiment 5
(2S, 3aR, 7aS)-1-[(2S)-2-[[(1S)-and 1-(ethoxycarbonyl)-3-hydrocinnamyl] amino]-the 1-oxopropyl] octahydro-1H-Indoline-2-carboxylic acid (Trolapril) (2g, 4.6mmol) the middle chloroform 20ml that adds, 61 ℃ are reacted 24h down, cross post and get white solid 1.1g, yield: 58%, 141～143 ℃ of fusing points.MS(m/z)：435(M+Na)
+；847(2M+Na)
+。
Embodiment 6
(2S, 3aR, 7aS)-1-[(2S)-2-[[(1S)-and 1-(ethoxycarbonyl)-3-hydrocinnamyl] amino]-the 1-oxopropyl] octahydro-1H-Indoline-2-carboxylic acid (Trolapril) (10g, add toluene 20ml 23mmol), 90 ℃ are reacted 20h down, evaporated under reduced pressure gets white solid 9.0g, yield: 94%, and 141～143 ℃ of fusing points.MS(m/z)：435(M+Na)
+；847(2M+Na)
+。
Embodiment 7
(2S, 3aR, 7aS)-1-[(2S)-2-[[(1S)-and 1-(ethoxycarbonyl)-3-hydrocinnamyl] amino]-the 1-oxopropyl] octahydro-1H-Indoline-2-carboxylic acid (Trolapril) (10g, add benzene 20ml 23mmol), 80 ℃ are reacted 20h down, evaporated under reduced pressure gets white solid 8.7g, yield: 91%, and 140～142 ℃ of fusing points.MS(m/z)：435(M+Na)
+；847(2M+Na)
+。
Claims (5)
1. the preparation method of Trandolapril diketone comprises Trolapril is reacted in soluble organic solvent, and wherein temperature of reaction is the boiling point of being less than or equal to this organic solvent, promptly gets Trandolapril diketone.
2. preparation method as claimed in claim 1, wherein said organic solvent is toluene, benzene, methylene dichloride, chloroform or ethyl acetate.
3. preparation method as claimed in claim 2, wherein said organic solvent is a toluene.
4. preparation method as claimed in claim 1, wherein said temperature of reaction are 70～110 ℃.
5. preparation method as claimed in claim 1, wherein the reaction times of this reaction is 1～24 hour.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007100404217A CN101302218B (en) | 2007-05-08 | 2007-05-08 | Preparation of Trandolapril diketone |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007100404217A CN101302218B (en) | 2007-05-08 | 2007-05-08 | Preparation of Trandolapril diketone |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101302218A CN101302218A (en) | 2008-11-12 |
| CN101302218B true CN101302218B (en) | 2011-02-23 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2007100404217A Expired - Fee Related CN101302218B (en) | 2007-05-08 | 2007-05-08 | Preparation of Trandolapril diketone |
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|---|---|
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4933361A (en) * | 1981-12-29 | 1990-06-12 | Hoechst Aktiengesellschaft | Derivatives of bicyclic aminoacids agents containing these compounds and their use |
-
2007
- 2007-05-08 CN CN2007100404217A patent/CN101302218B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4933361A (en) * | 1981-12-29 | 1990-06-12 | Hoechst Aktiengesellschaft | Derivatives of bicyclic aminoacids agents containing these compounds and their use |
Non-Patent Citations (2)
| Title |
|---|
| C.J.Blankley J.S.Kaltenbronn |
| C.J.Blankley,J.S.Kaltenbronn,D.E.Dejohn er al..synthesis and structure-activity relationships of potent newangiotensin converting enzyme inhibitors containing saturatedbicycloic amino acids.J.MED.CHEM30.1987,30992-998. * |
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|---|---|
| CN101302218A (en) | 2008-11-12 |
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