CN101560204A - Antihypertensive drug cilazapril intermediate and preparation method thereof - Google Patents
Antihypertensive drug cilazapril intermediate and preparation method thereof Download PDFInfo
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- CN101560204A CN101560204A CNA2009100513270A CN200910051327A CN101560204A CN 101560204 A CN101560204 A CN 101560204A CN A2009100513270 A CNA2009100513270 A CN A2009100513270A CN 200910051327 A CN200910051327 A CN 200910051327A CN 101560204 A CN101560204 A CN 101560204A
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- cilazapril
- antihypertensive drug
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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
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 obtain the 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, simplifies 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), be converted to Angiotensin II (Ang II) with strong vasoconstriction effect thereby suppress angiotensin I (Ang I).Make peripheral vascular resistance reduce 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 by the compound of the compound racemize structural formula 6 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.Reported again that in patent US651211 the compound of structural formula 7 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 is used to prepare Yipingshu, has avoided the post separation method excessively in the follow-up work, has simplified synthesis technique, reduce the three wastes, be applicable to suitability for industrialized production more.
Two of technical problem to be solved by this invention is to provide above-mentioned intermediates preparation.
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 by the compound that obtains structural formula 3 behind compound alkalization the removing L-tartrate to structural formula 2, the condensation reaction of the compound generation N1 position of the compound isostructure formula 4 of structural formula 3 obtains the compound of SS configuration structural formula 1.
Sodium bicarbonate, yellow soda ash 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, under the effect of hydrogen chloride gas, remove tertiary butyl protecting group at last and obtain antihypertensive drug Yipingshu 13.
The present invention has obtained the new compound 1 of a single SS configuration owing to adopted " preceding fractionation " method, 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 applicable to suitability for industrialized production more.
Embodiment
Embodiment 1
The preparation of the compound N of structural formula 4-O-phthalic amido-L-L-glutamic acid acid anhydride, concrete reaction formula is as follows:
L-L-glutamic acid 20g and N-ethoxycarbonyl O-phthalic acid imide 31.9g join among the aqueous solution 360ml that contains yellow soda ash 28.8g successively.Stirring at room is used ethyl acetate extraction then.After the water layer 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 obtains the buttery product, and the water recrystallization gets white solid product N-O-phthalic amido-L-L-glutamic acid 19.0g fusing point: 153-154 ℃
N-O-phthalic amido-L-L-glutamic acid 18.5g is dissolved among the diacetyl oxide 53.1g, be heated to then 110 ℃ 5 minutes.Concentrate, add ether.Get white solid product 16.5g, fusing point 202-204 ℃, optically-active: [α] after the 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, splash into the tetrahydrofuran solution 30ml of the compound of 7.1g structural formula 4 then, stirring at room half an hour, after reacting completely, with 30ml ethyl acetate extraction water layer, the water layer after the extraction is cooled to 0-5 ℃, with concentrated hydrochloric acid adjust pH=3, separate out white solid, obtain compound 1 10.8g after the filtration.MS：(M+Na)
+＝468
+
Embodiment 3
The 33.5g sodium bicarbonate is dissolved in the 350ml water, splash into the tetrahydrofuran solution 150ml of the compound of 44.8g structural formula 2, the tetrahydrofuran solution 50ml that adds the compound of 34.5g structural formula 4 then, after the stirring at room one hour, with 60ml ethyl acetate extraction water layer, the water layer after the extraction is cooled to 0-5 ℃, with concentrated hydrochloric acid adjust pH=3.5, separate out a large amount of white solids, get 55.5g compound 1 after the filtration.MS：(M+Na)
+＝468
+
Embodiment 4
The compound of 4.0g structural formula 2 is dissolved in the 30ml water, after adding the 30ml methylene dichloride, splash into the sodium hydroxide solution 18ml of 2M, stir the back layering, the water layer dichloromethane extraction, merge organic layer after, dry, be concentrated into dried, add the tetrahydrofuran solution of the compound of 3.0g structural formula 4, the after-filtration that reacts completely gets white solid product 3.5g.。MS：(M+Na)
+＝468
+
Embodiment 5
The compound of 2.0g structural formula 2 is dissolved in the 20ml water, after adding the 20ml methylene dichloride, splash into the sodium hydroxide solution 9ml of 2M, stir the back layering, the water layer dichloromethane extraction, merge organic layer after, dry, be concentrated into dried, the dichloromethane solution that adds the compound of 1.5g structural formula 4, be concentrated into after reacting completely dried filter white solid product 2.1g.MS：(M+Na)
+＝468
+
Embodiment 6
The compound of 10.3g structural formula 2 is dissolved in the 50ml water, after adding the 50ml methylene dichloride, splash into the sodium hydroxide solution 45ml of 2M, stir the back layering, the water layer dichloromethane extraction, merge organic layer after, dry, be concentrated into dried, the ethyl acetate solution that adds the compound of 7.5g structural formula 4, be concentrated into after reacting completely dried filter white solid product 11.4g.MS：(M+Na)
+＝468
+
The compound of structural formula 8 (1S, 9S)-the 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 the toluene, add then 5 normal 2, 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, concentrate yellow solid product.
The compound of structural formula 9 (1S, 9S)-the 1-tertiary butyl-9-(1,3-dioxy-2-pseudoindoyl)-10-oxo-8H-pyridazine [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 the exsiccant tetrahydrofuran (THF), cooling, nitrogen protection.Temperature after the tetrahydrofuran solution 7.5.ml of 1M borine slowly adds can keep one hour at 10-15 ℃, and reaction solution stirred stirring at room 3 hours one hour at 10-15 ℃ then.Methylene dichloride adds, and stirs to add 2M hydrochloric acid soln 17ml down.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 the drying then.
The preparation of the compound of structural formula 13 (Yipingshu monohydrate):
Embodiment 10
The compound 4.2g of structural formula 9 is dissolved in the ethanol, adds 85% hydrazine hydrate.Stirred one hour under the room temperature, concentrate, add toluene and continue to be concentrated into dried.The aqueous acetic acid that adds 2M stirs 16h, filters then.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.React completely postcooling to room temperature, add 30ml water, behind 1M sodium carbonate solution accent Ph=8.8, layering, organic layer is washed with 30ml, is concentrated into dried 5.3g oily matter after the drying, after adding the 30ml methylene dichloride, be cooled to-5 ℃, feed 3 hours exsiccant hydrogen chloride gas, stirring at room concentrated after 12 hours then.Enriched material adds entry and isopropyl ether, and the hydrochloric acid soln with 1M extracts then.Concoct water layer Ph=4.4 also with the sodium hydroxide solution of 5M then.Obtain hila pula monohydrate after the filtration, filtrate obtains second batch of product Yipingshu after with dichloromethane extraction, and m.p 95-97 ℃, [a]
D 20-62.51 (C 1 in ethanol).
Claims (3)
1. an antihypertensive drug cilazapril intermediate is characterized in that, is the compound of following structural formula 1:
2. the preparation method of the described antihypertensive drug cilazapril intermediate of claim 1, it is characterized in that by the compound that obtains structural formula 3 behind compound alkalization the removing L-tartrate to structural formula 2 condensation reaction of the compound generation N1 position of the compound isostructure formula 4 of structural formula 3 obtains the compound of SS configuration structural formula 1
3. preparation method as claimed in claim 1 is characterized in that, sodium bicarbonate, yellow soda ash or sodium hydroxide solution 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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| CN101560204B CN101560204B (en) | 2013-11-13 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8785431B2 (en) | 2011-06-22 | 2014-07-22 | Hexal Ag | Prodrugs 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 use in transdermal therapeutic systems |
| CN109438449A (en) * | 2018-11-16 | 2019-03-08 | 厦门医学院 | A kind of synthetic method of the Cilazapril of the structure of acid containing hexahydro-pyridazine |
| CN109467550A (en) * | 2017-12-31 | 2019-03-15 | 苏州亚科科技股份有限公司 | A kind of synthetic method of phthalyl amido-Pidolidone acid anhydride |
-
2009
- 2009-05-15 CN CN2009100513270A patent/CN101560204B/en active Active
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8785431B2 (en) | 2011-06-22 | 2014-07-22 | Hexal Ag | Prodrugs 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 use in transdermal therapeutic systems |
| CN109467550A (en) * | 2017-12-31 | 2019-03-15 | 苏州亚科科技股份有限公司 | A kind of synthetic method of phthalyl amido-Pidolidone acid anhydride |
| 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 |
| CN109438449A (en) * | 2018-11-16 | 2019-03-08 | 厦门医学院 | A kind of synthetic method of the Cilazapril of the structure of acid containing hexahydro-pyridazine |
| 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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| CN101560204B (en) | 2013-11-13 |
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