CN100569749C - The preparation method of 4-carbonyl-(S)-proline derivative - Google Patents
The preparation method of 4-carbonyl-(S)-proline derivative Download PDFInfo
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- CN100569749C CN100569749C CNB200510030291XA CN200510030291A CN100569749C CN 100569749 C CN100569749 C CN 100569749C CN B200510030291X A CNB200510030291X A CN B200510030291XA CN 200510030291 A CN200510030291 A CN 200510030291A CN 100569749 C CN100569749 C CN 100569749C
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- proline derivative
- carbonyl
- tetramethyl
- free radical
- nitroxyl free
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Abstract
The invention provides the method for a kind of synthetic antihypertensive drug spirapril intermediate 4-carbonyl-(S)-proline derivative.Spirapril is a kind of antihypertensive drug of long-acting, powerful ACEI class.The present invention is a raw material with 4-hydroxyl-L-proline derivative, 2,2,6, under the catalysis of 6-tetramethyl-nitroxyl free radical piperidines, obtains 4-carbonyl-(S)-proline derivative with oxidant reaction.This method is easy, yield is high, the reaction conditions gentleness, and environmental friendliness is easy to large-scale production.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to the synthetic method of pharmaceutical intermediate 4-carbonyl-(S)-proline derivative.
Background technology
4-carbonyl-(S)-proline derivative is the important pharmaceutical intermediate of a class, can be used for for example spirapril synthetic of some medicines, and it is obtained through oxidation by 4-hydroxyl-L-proline derivative usually.
About described structure oxidization of intermediates process, what have bibliographical information now mainly contains three kinds:
1.Swern oxidation [JOC, 1992,57 (19): 5264-8 etc.];
The main drawback of this method is to need cold operation, and the condition harshness to the equipment requirements height, is not suitable for suitability for industrialized production.
2. Jones reagent oxidation [J.Am.Chem.Soc., 1957,79 (5): 185-192];
Or [JOC, 2001,66 (10): 3593-3596].
The open defect of this method is exactly the significant damage of heavy metal chromium for environment and human health, therefore also is not suitable for suitability for industrialized production.
3. precious metal catalyst oxidation [seeing German Patent DD283626];
This method catalyst system therefor costs an arm and a leg, and the cost height is not suitable for suitability for industrialized production.
At present 4-hydroxyl-L-proline derivative is obtained in the technology of 4-carbonyl-(S)-proline derivative the main technical problem that exists as mentioned above through oxidation, perhaps operational condition harshness, perhaps reaction reagent harm environment and human health, perhaps technology cost costliness etc.All be not suitable for suitability for industrialized production.
Summary of the invention
The object of the present invention is to provide the described 4-hydroxyl of a kind of oxidation-L-proline derivative to obtain the method for 4-carbonyl-(S)-proline derivative, the defective that it can overcome on the prior art provides the processing condition that more help the industrialization operation.
Method of the present invention comprises following concrete steps:
With 4-hydroxyl-L-proline derivative, TEMPO or 4-methoxyl group-2,2,6,6-tetramethyl-nitroxyl free radical piperidines, oxygenant add in the solvent, and reaction 5 minutes-5 hours is complete to substrate reactions down at-25 ℃-100 ℃.Reaction is removed excess oxidant with sodium sulfite solution after finishing, and the washing back concentrates and can obtain oxidation products, yield 84-90%.
Employed raw material among the present invention, reagent are cheap and easy to get, and cost is low; This method is easy and simple to handle, and reaction is carried out at ambient temperature, and is comparatively gentle; This reaction required time is short, and chemo-selective is good, and other groups are not had influence.The oxidation products purity height that obtains need not purifying and directly drops into next step reaction.In addition, this method also has the free of contamination advantage of clean environment firendly.Therefore be a kind of processing method that is fit to very much suitability for industrialized production.
Embodiment
The present invention is further elaborated below in conjunction with embodiment, but these embodiment do not constitute any restriction to the present invention.
Embodiment one
With C
2H
5Oxyproline 0.45g, 5%NaClO solution 5ml, the 4-methoxyl group-2 of OCO protection; 2; 6; 6-tetramethyl-nitroxyl free radical piperidines 0.001g adds in the 5ml solvent; down reaction 5 minutes-5 hours is complete to substrate reactions at-25 ℃-100 ℃; then remove excessive oxygenant with sodium sulfite solution, the washing back concentrates and promptly gets oxidation products, yield 90%.
Embodiment two
Oxyproline 0.50g, 5%NaBrO solution 6ml, 2 with the PNB protection; 2; 6; 6-tetramethyl-nitroxyl free radical piperidines (TEMPO) 0.03g adds in the 5ml solvent; down reaction 5 minutes-50 minutes is complete to substrate reactions at 25 ℃-50 ℃; then remove excessive oxygenant with sodium sulfite solution, the washing back concentrates and promptly obtains oxidation products, yield 88%.
Embodiment three
Oxyproline 0.12g, TCCA (Trichloroisocyanuric acid) (TCCA) 0.23g, 2 with the Cbz protection; 2; 6; 6-tetramethyl-nitroxyl free radical piperidines (TEMPO) 0.007g adds in the 2ml solvent; down reaction 15 minutes-95 minutes is complete to substrate reactions at-25 ℃-25 ℃; then remove excessive oxygenant with sodium sulfite solution, the washing back concentrates and promptly obtains oxidation products, yield 86%.
Embodiment four
Oxyproline 0.25g, TCCA (Trichloroisocyanuric acid) (TCCA) 0.48g, 4-methoxyl group-2 with the Cbz protection; 2; 6; 6-tetramethyl-nitroxyl free radical piperidines 0.02g adds in the 3ml solvent; down reaction 15 minutes-95 minutes is complete to substrate reactions at-25 ℃-25 ℃; then remove excessive oxygenant with sodium sulfite solution, the washing back concentrates and promptly obtains oxidation products, yield 84%.
Embodiment five
Oxyproline 0.32g, N-chlorosuccinimide (NCS) 0.37g, 4-methoxyl group-2 with the Boc protection; 2; 6; 6-tetramethyl-nitroxyl free radical piperidines 0.01g adds in the 3ml solvent; react 5 minutes-5 hours down to the substrate complete reaction at-25 ℃-100 ℃; then remove excessive oxygenant with sodium sulfite solution, the washing back concentrates and promptly obtains oxidation products, yield 90%.
Embodiment six
With CH
3Oxyproline 0.36g, N-bromo-succinimide (NBS) 0.67g of OCO protection; 2; 2; 6; 6-tetramethyl-nitroxyl free radical piperidines (TEMPO) 0.02g adds in the 3ml solvent, reacts 5 minutes-5 hours down to the substrate complete reaction at-25 ℃-100 ℃, then removes excessive oxygenant with sodium sulfite solution; the washing back concentrates and promptly obtains oxidation products, yield 88%.
Embodiment seven
Oxyproline 4.20g, hydrogen peroxide 14ml with the Fmoc protection; 2; 2; 6; 6-tetramethyl-nitroxyl free radical piperidines (TEMPO) 0.002g adds in the 3ml solvent, reacts 5 minutes-5 hours down to the substrate complete reaction at-25 ℃-100 ℃, then removes excessive oxygenant with sodium sulfite solution; the washing back concentrates and promptly obtains oxidation products, yield 85%.
More than show and described ultimate principle of the present invention and principal character and advantage of the present invention.The technician of the industry should understand; the present invention is not restricted to the described embodiments; that describes in the foregoing description and the specification sheets just illustrates principle of the present invention; the present invention also has various changes and modifications without departing from the spirit and scope of the present invention, and these changes and improvements all fall in the claimed scope of the invention.The claimed scope of the present invention is defined by appending claims and equivalent thereof.
Claims (4)
1. method from the synthetic 4-carbonyl of 4-hydroxyl-L-proline derivative (I)-(S)-proline derivative (II), it is characterized in that, 4-hydroxyl-L-proline derivative (I) is at catalyzer 2,2,6, under the effect of 6-tetramethyl-nitroxyl free radical piperidines, obtain 4-carbonyl-(S)-proline derivative (II), be shown below with oxidant reaction;
In the formula:
The amino formate of R=amino formate or replacement,
Oxygenant is selected from N-chlorosuccinimide, N-bromo-succinimide or TCCA (Trichloroisocyanuric acid).
2, method according to claim 1, the amino formate that it is characterized in that described replacement be carbobenzoxy-(Cbz), tertbutyloxycarbonyl, to nitro carbobenzoxy-(Cbz), methoxycarbonyl, ethoxycarbonyl or 9-fluorenylmethyloxycarbonyl.
3. synthetic method according to claim 1 is characterized in that described catalyzer 2,2,6, and 6-tetramethyl-nitroxyl free radical piperidines comprises:
Respectively suc as formula 2,2,6 shown in (III) and the formula (IV), 6-tetramethyl-nitroxyl free radical piperidines and 4-methoxyl group-2,2,6,6-tetramethyl-nitroxyl free radical piperidines.
4. method according to claim 1 is characterized in that, wherein the mol ratio of the catalyzer that adopts and substrate be 1 ‰～10%.
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| CNB200510030291XA CN100569749C (en) | 2005-09-30 | 2005-09-30 | The preparation method of 4-carbonyl-(S)-proline derivative |
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| CNB200510030291XA CN100569749C (en) | 2005-09-30 | 2005-09-30 | The preparation method of 4-carbonyl-(S)-proline derivative |
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| CN1939904A CN1939904A (en) | 2007-04-04 |
| CN100569749C true CN100569749C (en) | 2009-12-16 |
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Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101445475B (en) * | 2008-12-30 | 2010-12-22 | 浙江工业大学 | Method for preparing (trans)-4-cyclohexyl-L-proline |
| CN102101849B (en) * | 2011-03-10 | 2013-06-05 | 广州诺浩医药科技有限公司 | Preparation method of clausenamide intermediate |
| CN104788353B (en) * | 2015-04-07 | 2018-04-20 | 四川同晟氨基酸有限公司 | A kind of method for synthesizing 4 oxo L proline derivatives |
| CN105153005A (en) * | 2015-08-05 | 2015-12-16 | 上海瑞博化学有限公司 | Preparation method of 4-carbonyl-proline derivative |
| EP3564226B1 (en) | 2016-12-27 | 2021-06-02 | Kao Corporation | Method for producing glyceric acid ester |
| JP6405443B2 (en) * | 2016-12-27 | 2018-10-17 | 花王株式会社 | Process for producing 1,3-dioxane-5-ones |
| AU2017388710B2 (en) * | 2016-12-27 | 2019-04-04 | Kao Corporation | Method for manufacturing 1,3-dioxane-5-one |
| US10829482B2 (en) | 2016-12-27 | 2020-11-10 | Kao Corporation | Method for producing glyceric acid ester |
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2005
- 2005-09-30 CN CNB200510030291XA patent/CN100569749C/en not_active Expired - Fee Related
Non-Patent Citations (6)
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| Method for preparation of aromatic ketone or aldehyde.. CA136:385940. 2000 |
| Method for preparation of aromatic ketone or aldehyde.. CA136:385940. 2000 * |
| 一种快速无污染高收率的氧化法制备醛和酮. 王哲清.中国医药工业杂志，第31卷第1期. 2000 |
| 一种快速无污染高收率的氧化法制备醛和酮. 王哲清.中国医药工业杂志，第31卷第1期. 2000 * |
| 醇的催化氧化研究进展. 康巧香，杨志旺，雷自强.化学研究，第15卷第2期. 2004 |
| 醇的催化氧化研究进展. 康巧香，杨志旺，雷自强.化学研究，第15卷第2期. 2004 * |
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