CN101560204B - Antihypertensive drug cilazapril intermediate and preparation method thereof - Google Patents
Antihypertensive drug cilazapril intermediate and preparation method thereof Download PDFInfo
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- CN101560204B CN101560204B CN2009100513270A CN200910051327A CN101560204B CN 101560204 B CN101560204 B CN 101560204B CN 2009100513270 A CN2009100513270 A CN 2009100513270A CN 200910051327 A CN200910051327 A CN 200910051327A CN 101560204 B CN101560204 B CN 101560204B
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- cilazapril
- antihypertensive drug
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- 0 CC(CCC*NN)[C@](*=O)O*(C)C Chemical compound CC(CCC*NN)[C@](*=O)O*(C)C 0.000 description 9
- MKVDMPWPXMSYAC-LBPRGKRZSA-N CCCOC([C@H](CCc1ccccc1)N)=O Chemical compound CCCOC([C@H](CCc1ccccc1)N)=O MKVDMPWPXMSYAC-LBPRGKRZSA-N 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
An antihypertensive drug cilazapril intermediate is the compound of the structural formula 1, which is obtained by the steps of alkalising the compound of structural formula 2 to remove L-tartaric acid and obtaining the compound of structural formula 3, subjecting the compound of structural formula 3 and the compound of structural formula 4 to a reaction to obtain a single SS-configuration compound 1 of structural formula 1. The compound of structural formula 1 in the invention is cyclized to obtain the compound of structural formula 8. The compound of structural formula 8 is processed by reduction through borane, protective group removal and suprafacial chain condensation, and is processed by tertiary butyl protective group removal under the action of hydrochloric acid gas so as to obtainthe antihypertensive drug cilazapril 13. The invention uses front split, obtains a single SS-configuration new compound of structural formula 1, avoids column-passing spit in subsequent procedures, s implifies synthesis technology, decreases cost, and reduces three wastes. Thus, the invention is more suitable for commercial production.
Description
Technical field
The present invention relates to prepare antihypertensive drug cilazapril intermediate and preparation method.
Background technology
Yipingshu is a kind of specific long-acting angiotensin converting enzyme inhibitor, can suppress renin-angiotensin-aldosterone system (RAAS), thereby suppress angiotensin I (AngI), be converted to the Angiotensin II (AngII) with strong vasoconstriction effect.Peripheral vascular resistance is reduced, blood pressure drops.The essential hypertension and the renal hypertension that are used for the treatment of various degree.Also can share chronic heart failure with purple foxglove or hydragog(ue).
The method for preparing at present Yipingshu has following several:
Described the preparation method who is prepared the compound of racemize structural formula 6 by the compound of the compound isostructure formula 4 of structural formula 5 in patent US6201118 or US6512111, then the compound of racemize structural formula 6 obtains the compound of structural formula 7 through cyclization.The compound of having reported again structural formula 7 in patent US651211 obtains the compound of the structural formula 8 of SS configuration through column chromatography.
Above-mentioned route method existed the post complex process, was not suitable for suitability for industrialized production, and three waste discharge is many, contaminate environment.
Summary of the invention
One of technical problem to be solved by this invention is to provide a kind of antihypertensive drug cilazapril intermediate, this intermediate, for the preparation of Yipingshu, has been avoided the post separation method excessively in the follow-up work, has simplified synthesis technique, reduce the three wastes, be more applicable for suitability for industrialized production.
Two of technical problem to be solved by this invention is to provide the preparation method of above-mentioned intermediate.
A kind of antihypertensive drug cilazapril intermediate as first aspect present invention is the compound of following structural formula 1:
Preparation method as the above-mentioned antihypertensive drug cilazapril intermediate of second aspect present invention, be to remove after L-TARTARIC ACID by the compound to structural formula 2 alkalization the compound that obtains structural formula 3, the condensation reaction that the N1 position occurs the compound of the compound isostructure formula 4 of structural formula 3 obtains the compound of SS configuration structural formula 1.
Sodium bicarbonate, sodium carbonate or sodium hydroxide solution are adopted in described alkalization.
The compound of structural formula 1 of the present invention obtains the compound of structural formula 8 through cyclization; the compound of structural formula 8 can be through borane reduction, go protecting group, then with the side chain condensation, remove tertiary butyl protecting group finally under the effect of hydrogen chloride gas and obtain antihypertensive drug Yipingshu 13.
The present invention, owing to having adopted " front fractionation " method, has obtained the new compound 1 of a single SS configuration, has avoided the post of crossing in the follow-up work to split, and has simplified synthesis technique, has reduced cost, has reduced the three wastes, thereby be more applicable for suitability for industrialized production.
Embodiment
Embodiment 1
The preparation of the compound N of structural formula 4-O-phthalic amido-Pidolidone acid anhydride, concrete reaction formula is as follows:
Pidolidone 20g and N-ethoxycarbonyl O-phthalic acid imide 31.9g join in the aqueous solution 360ml that contains sodium carbonate 28.8g successively.Stirring at room, then use ethyl acetate extraction.After water layer is cooling, with hydrochloric acid, water is transferred to pH=2, then ethyl acetate extraction, saturated nacl aqueous solution is washed, and drying is filtered, concentrating under reduced pressure, obtain the product of oily, and the water recrystallization obtains white solid product N-O-phthalic amido-Pidolidone 19.0g fusing point: 153-154 ℃
N-O-phthalic amido-Pidolidone 18.5g is dissolved in diacetyl oxide 53.1g, then be heated to 110 ℃ 5 minutes.Concentrated, add ether.Obtain white solid product 16.5g, fusing point 202-204 ℃, optically-active: [α] after filtration
D 21-43.1 ° (c 1.75 in dioxane)
Embodiment 2
The compound of structural formula 1 (2S)-5-[(S)-3-(tetrahydrochysene-3-tertbutyloxycarbonyl) pyridazinyl-1-yl]-preparation of 2-(1,3-dioxo-2H-isoindole-2-yl)-5-oxopentanoic acid
Embodiment 2
9.2g the compound of structural formula 2 adds the 40ml tetrahydrofuran (THF), stirring is a suspension solution, slowly splash into 140ml 5% sodium hydrogen carbonate solution alkalization and remove L-type tartrate, then splash into the tetrahydrofuran solution 30ml of the compound of 7.1g structural formula 4, stirring at room half an hour, after reacting completely, with 30ml ethyl acetate extraction water layer, the water layer after extraction is cooled to 0-5 ℃, with concentrated hydrochloric acid adjust pH=3, separate out white solid, obtain compound 1 10.8g after filtration.MS：(M+Na)
+＝468
+
Embodiment 3
The 33.5g sodium bicarbonate is dissolved in 350ml water, splash into the tetrahydrofuran solution 150ml of the compound of 44.8g structural formula 2, then the tetrahydrofuran solution 50ml that adds the compound of 34.5g structural formula 4, after stirring at room one hour, with 60ml ethyl acetate extraction water layer, the water layer after extraction is cooled to 0-5 ℃, with concentrated hydrochloric acid adjust pH=3.5, separate out a large amount of white solids, obtain 55.5g compound 1 after filtration.MS：(M+Na)
+＝468
+
Embodiment 4
The compound of 4.0g structural formula 2 is dissolved in 30ml water, after adding the 30ml methylene dichloride, splash into the sodium hydroxide solution 18ml of 2M, layering after stirring, the water layer dichloromethane extraction, after merging organic layer, dry, be concentrated into dried, the tetrahydrofuran solution that adds the compound of 3.0g structural formula 4, filter to obtain white solid product 3.5g after reacting completely.。MS：(M+Na)
+＝468
+
Embodiment 5
The compound of 2.0g structural formula 2 is dissolved in 20ml water, after adding the 20ml methylene dichloride, splash into the sodium hydroxide solution 9ml of 2M, layering after stirring, the water layer dichloromethane extraction, after merging organic layer, dry, be concentrated into dried, the dichloromethane solution that adds the compound of 1.5g structural formula 4, be concentrated into the dried white solid product 2.1g that filters to obtain after reacting completely.MS：(M+Na)
+＝468
+
Embodiment 6
The compound of 10.3g structural formula 2 is dissolved in 50ml water, after adding the 50ml methylene dichloride, splash into the sodium hydroxide solution 45ml of 2M, layering after stirring, the water layer dichloromethane extraction, after merging organic layer, dry, be concentrated into dried, the ethyl acetate solution that adds the compound of 7.5g structural formula 4, be concentrated into the dried white solid product 11.4g that filters to obtain after reacting completely.MS：(M+Na)
+＝468
+
The compound (1S, 9S) of the structural formula 8-1-tertiary butyl-9-(1,3-dioxy-2-pseudoindoyl)-6,10-dioxo-8H-pyridazine is [1,2-a] [1,2] diaza also
The preparation of-1-carboxylicesters:
Embodiment 7
The compound of structural formula 1 is dissolved in toluene, then adds 2 of 5 equivalents, the 6-lutidine.Reaction solution is heated to 70 ℃, with the toluene solution that slowly added 2 equivalent sulfur oxychlorides and 0.1 equivalent DMF in two hours.Reaction solution with dilution with toluene after, filter, organic layer is respectively with sodium bicarbonate and saturated common salt washing, anhydrous sodium sulfate drying, the concentrated yellow solid product that to obtain.
The compound (1S, 9S) of the structural formula 9-1-tertiary butyl-9-(1,3-dioxy-2-pseudoindoyl)-10-oxo-8H-pyridazine is [1,2-a] [1,2] diaza also
The preparation of-1-carboxylicesters:
Embodiment 9
The compound 3.6g of structural formula 8 is dissolved in dry tetrahydrofuran (THF), and is cooling, nitrogen protection.Temperature after the tetrahydrofuran solution 7.5.ml of 1M borine slowly adds can keep one hour at 10-15 ℃, and then reaction solution stirred one hour at 10-15 ℃, stirring at room 3 hours.Methylene dichloride adds, and adds 2M hydrochloric acid soln 17ml under stirring.Then with after the anhydrous sodium carbonate alkalization, organic layer is washed with saturated salt, is concentrated into the dried product 3.5g that obtains after drying.
The preparation of the compound of structural formula 13 (Yipingshu monohydrate):
Embodiment 10
The compound 4.2g of structural formula 9 is dissolved in ethanol, adds 85% hydrazine hydrate.Stirred one hour under room temperature, concentrated, add toluene to continue to be concentrated into dried.The aqueous acetic acid that adds 2M, stir 16h, then filters.After the sodium bicarbonate alkalization, dichloromethane extraction.Being concentrated into the dried 2.9g of obtaining oily matter and being dissolved in dichloroethane solution 25ml, join the ethylene dichloride 25ml of side chain, N-methylmorpholine, be heated to 85 ℃, is a red solution, stirs 12 hours.Be cooled to room temperature after reacting completely, add 30ml water, after transferring Ph=8.8 with the 1M sodium carbonate solution, layering, organic layer is washed with 30ml, is concentrated into dried 5.3g oily matter after drying, after adding the 30ml methylene dichloride, be cooled to-5 ℃, pass into 3 hours dry hydrogen chloride gas, then stirring at room is concentrated after 12 hours.Enriched material adds water and isopropyl ether, then with the hydrochloric acid soln of 1M, extracts.Then concoct water layer Ph=4.4 also with the sodium hydroxide solution of 5M.Obtain hila pula monohydrate after filtration, filtrate obtains second batch product Yipingshu, m.p 95-97 ℃, [a] after with dichloromethane extraction
D 20-62.51 (C 1 in ethanol).
Claims (2)
1. the preparation method of an antihypertensive drug cilazapril intermediate, it is characterized in that removing after L-TARTARIC ACID by the compound to structural formula 2 alkalization the compound that obtains structural formula 3, the condensation reaction that the N1 position occurs the compound of the compound isostructure formula 4 of structural formula 3 obtains the compound of SS configuration structural formula 1
2. preparation method as claimed in claim 1, is characterized in that, sodium bicarbonate, sodium carbonate or sodium hydroxide solution are adopted in described alkalization.
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| CN2009100513270A CN101560204B (en) | 2009-05-15 | 2009-05-15 | Antihypertensive drug cilazapril intermediate and preparation method thereof |
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| CN2009100513270A CN101560204B (en) | 2009-05-15 | 2009-05-15 | Antihypertensive drug cilazapril intermediate and preparation method thereof |
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| CN101560204A CN101560204A (en) | 2009-10-21 |
| CN101560204B true CN101560204B (en) | 2013-11-13 |
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Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| EP2537534B1 (en) | 2011-06-22 | 2014-12-17 | Hexal AG | Esters of (1S,9S)-9-[[(1S)-1-carboxy-3-phenylpropyl]amino]octahydro-10-oxo-6H-pyridazino[1,2-a][1,2]diazepine-1-carboxylic acid and their therapeutic use. |
| CN109467550B (en) * | 2017-12-31 | 2022-02-18 | 苏州亚科科技股份有限公司 | Synthesis method of phthalic diamide-L-glutamic anhydride |
| CN109438449B (en) * | 2018-11-16 | 2020-08-11 | 厦门医学院 | Synthesis method of cilazapril containing hexahydropyridazine acid structure |
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