CN103788084A - Tetrahydroisoquinoline derivative and synthesis method thereof - Google Patents
Tetrahydroisoquinoline derivative and synthesis method thereof Download PDFInfo
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Abstract
The invention discloses a tetrahydroisoquinoline derivative and a synthesis method thereof. The name of the compound is ethyl-5-iodine-2-(8-(substituted phenyl amino formoxyl)-3,4-dihydrogen isoquinoline-2 (1H)-yl) thiazole-4-Nonanoic acid-ethyl ester. The target product is obtained from 2-benzyl-1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid as an initial raw material by debenzylation, substitution, acylation and condensation. The compound has potential biological activity.
Description
Technical field
The present invention relates to the novel preparation method of tetrahydro isoquinoline derivative; be particularly related to iodo-2 – of compound ethyl-5-(8-(substituted-phenyl formamyl)-3; 4-dihydro-isoquinoline-2 (1H)-yl)-4, a kind of preparation method of 5-thiazoline-4-carboxylic acid, ethyl ester.
Technical background
Iodo-2 – of compound ethyl-5-(8-(substituted-phenyl formamyl)-3,4-dihydro-isoquinoline-2 (1H)-yl)-4,5-thiazoline-4-carboxylic acid, ethyl ester, structural formula is:
The tetrahydroisoquinoliderivs derivs with structure complicated and changeable is the important component of modern medicines and the source of new drug development.They have hypertension, antimycotic, and anti-arrhythmia is antiviral, the biological activity widely such as antibacterial and very strong anti-oxidant activity.The found history of tetrahydroisoquinoliderivs derivs is not very very long, 1974, in the secondary metabolite that Portugal streptomycete (StreptomyceslusitanusAYB-1026) from soil such as Canada scientist Kluepfel produces, separate the tetrahydro isoquinoline derivative naphthyridinomycin that obtains first case and have anti-tumor activity.Up to the present, from plant, extract to separate and obtain approximately 60 and there is analog structure and active tetrahydro isoquinoline derivative.These natural products have stronger cytotoxicity mostly, aspect antitumor and antibacterials exploitation, have very large potentiality, and wherein ET-743 has unique antitumor action, are used for the treatment of soft-tissue tumor in 2007 in Germany and Britain's listing.But natural product content is low, cytotoxicity is large, the tetrahydro isoquinoline derivative that exploitation has a novel texture has attracted the interest of numerous synthetic chemistry man.
The primary structure feature of four atmosphere morphinane alkaloids is to contain this core skeleton structure of tetrahydroisoquinoline, four oxygen isoquinoline compounds are carried out to structure of modification and become the focus of domestic and international research, so the structure of tetrahydro isoquinoline compound is modified and is transformed, synthetic new tetrahydro isoquinoline compound also finds reaction conditions gentleness, and the methodology of organic synthesis with actual application value has important practical significance to the synthetic of tetrahydroisoquinoline alkaloid and derivative thereof.
The Chen Jie of Medical University Of Chongqing loyalty, journey instruction official rank people have done a large amount of work in the modification of tetrahydroisoquinoline ring.Mainly concentrate on by design synthetic route, the tetrahydro isoquinoline compound of synthetic 1 replacement, the people such as Chen Jiezhong design and have synthesized the four hydrogen isoquinoline hydrochloric acid salt that 1-chloromethyl replaces, and it is the important intermediate of synthetic antischistosomal drug quinoline ketone (praziquantel).Journey instruction official rank people designs and has synthesized the Tetrahydroisoquinoli-beautiful jade that 1-aminomethyl replaces, and it is the important intermediate of synthesizing antineoplastic medicament dish nitrogen pyrrole derivatives.
Compound involved in the present invention is the tetrahydro isoquinoline derivative that a class has new side chain structure, and these compounds have no other patent literatures at present.
Summary of the invention
The invention discloses tetrahydroisoquinoliderivatives derivatives and synthetic method thereof, with 2-benzyl-1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid is starting raw material, is prepared into target product through de-benzyl, replacement, acidylate, condensation four-step reaction, and synthetic route as shown in Figure 1.Synthesis step is as follows:
(1), with 2-benzyl-1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid (1) is starting raw material, takes off benzyl obtain 2 with debenzylation reagent;
(2) under alkaline condition, there is nucleophilic substitution reaction with the chloro-5-iodine of 2-4-thiazolecarboxylic acid ethyl ester 2, obtain 3;
(3) react and obtain 4 with chloride reagent 3;
(4) carry out condensation reaction 4 with corresponding substituted aniline, obtain 5.
Wherein, A is C
1-6alkyl, C
1-6alkoxyl group, hydrogen, halogen, cyano group, nitro.
One preferred embodiment in, described synthetic 1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid debenzylation reagent used is selected from palladium carbon-hydrogen; Described nucleophilic substitution reaction alkali used is selected from salt of wormwood; Described acyl chloride reaction acylating reagent used is selected from sulfur oxychloride; Described condensation reaction alkali used is selected from pyridine.
One preferred embodiment in, described synthetic 1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid solvent used is selected from methyl alcohol; Described nucleophilic substitution reaction solvent used is selected from DMF; Described acyl chloride reaction solvent used is selected from sulfur oxychloride; Described condensation reaction solvent used is selected from ethyl acetate.
One preferred embodiment in, the temperature of reaction of described synthetic 1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid is room temperature; The temperature of reaction of described nucleophilic substitution reaction is the reflux temperature of solvent; The temperature of reaction of described acyl chloride reaction is 0 ℃; The temperature of reaction of described condensation reaction is room temperature.
The present invention relates to iodo-2 – of ethyl-5-(8-(substituted-phenyl formamyl)-3; 4-dihydro-isoquinoline-2 (1H)-yl)-4; 5-thiazoline-4-carboxylic acid, ethyl ester and synthetic method thereof, do not have other Patents bibliographical informations at present.
Accompanying drawing explanation
Fig. 1 is iodo-2 – of ethyl-5-(8-(substituted-phenyl formamyl)-3,4-dihydro-isoquinoline-2 (1H)-yl)-4, the synthetic route chart of 5-thiazoline-4-carboxylic acid, ethyl ester.
The present invention is further described by the following embodiment, and these descriptions are not that content of the present invention is further limited.One skilled in the art will understand that the replacement that is equal to that technical characterictic of the present invention is done, or improve accordingly, within still belonging to protection scope of the present invention.
Specific embodiment mode
(1) 1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid synthetic
2-benzyl-1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid 100g joins in 2L methyl alcohol, then adds 10g10%Pd/C, pass into hydrogen, stirring at room temperature reaction 24 hours, stopped reaction, filters, after filtrate decompression is concentrated, obtain 1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid.
(2) 2-(4-(ethoxycarbonyl)-5-iodine thiazole-yl)-1,2,3,4-tetrahydroisoquinoline-8-formic acid synthetic
60g1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid, the chloro-5-iodine of 2-thiazole-4-carboxylic acid ethyl ester 90g, 55g Anhydrous potassium carbonate join 800ml N successively, in dinethylformamide, be heated to reflux, stir 10 hours, stopped reaction, most of DMF is removed in decompression, and residuum extracts separatory with ethyl acetate and water, collect organic phase, dry, concentrated rear upper silicagel column separates and obtains 136.8g2-(4-(ethoxycarbonyl)-5-iodine thiazole-yl)-1,2,3,4-tetrahydroisoquinoline-8-formic acid.
(3) ethyl 2-(8-(chloroformyl)-3,4-dihydro-isoquinoline-2 (1H)-yl)-5-iodine thiazole-4-carboxylic acid ethyl ester's is synthetic
120g2-(4-(ethoxycarbonyl)-5-iodine thiazole-yl)-1,2,3,4-tetrahydroisoquinoline-8-formic acid joins in the 1000ml sulfur oxychloride of 0 ℃, stir 6 hours, stopped reaction, sulfur oxychloride is removed in decompression, obtain 125g ethyl 2-(8-(chloroformyl)-3,4-dihydro-isoquinoline-2 (1H)-yl)-5-iodine thiazole-4-carboxylic acid ethyl ester.
(4) the iodo-2-of ethyl-5-(8-(phenyl amino formyl radical)-3,4-dihydro-isoquinoline-2 (1H)-yl) thiazole-4-carboxylic acid ethyl ester's is synthetic
30g aniline is joined in 800ml ethyl acetate, add again 50ml pyridine, be cooled to 0 ℃, be added dropwise to 125g ethyl 2-(8-(chloroformyl)-3, 4-dihydro-isoquinoline-2 (1H)-yl)-5-iodine thiazole-4-carboxylic acid ethyl ester, keep system temperature to be no more than 10 ℃, after dropwising, 0 ℃ is continued to stir 14 hours, reaction solution is slowly poured in frozen water, add dilute hydrochloric acid, stir, separatory, collect organic phase, dry, after concentrated, upper silicagel column separates and obtains the iodo-2-of 128.4g ethyl-5-(8-(phenyl amino formyl radical)-3, 4-dihydro-isoquinoline-2 (1H)-yl) thiazole-4-carboxylic acid ethyl ester.
H1-NMR(CDCl
3,400M):8.71(1H,brs),7.75～7.64(3H,m),7.33～7.24(4H,m),7.16(1H,m),4.25～4.09(4H,m),3.41(2H,t),2.64(2H,t),1.29(3H,t)。
The iodo-2-of ethyl-5-(8-(p-methylphenyl formamyl)-3,4-dihydro-isoquinoline-2 (1H)-yl) thiazole-4-carboxylic acid ethyl ester's is synthetic
35g is joined in 800ml ethyl acetate monomethylaniline, add again 50ml pyridine, be cooled to 0 ℃, be added dropwise to 125g ethyl 2-(8-(chloroformyl)-3, 4-dihydro-isoquinoline-2 (1H)-yl)-5-iodine thiazole-4-carboxylic acid ethyl ester, keep system temperature to be no more than 10 ℃, after dropwising, 0 ℃ is continued to stir 14 hours, reaction solution is slowly poured in frozen water, add dilute hydrochloric acid, stir, separatory, collect organic phase, dry, after concentrated, upper silicagel column separates and obtains the iodo-2-of 129.8g ethyl-5-(8-(p-methylphenyl formamyl)-3, 4-dihydro-isoquinoline-2 (1H)-yl) thiazole-4-carboxylic acid ethyl ester.
H1-NMR(CDCl
3,400M):8.72(1H,brs),7.76～7.65(3H,m),7.34～7.26(4H,m),7.17(1H,m),4.26～4.12(4H,m),3.42(2H,t),2.66(2H,t),2.31(3H,s),1.31(3H,t)。
The iodo-2-of ethyl-5-(8-(m-methoxyphenyl formamyl)-3,4-dihydro-isoquinoline-2 (1H)-yl) thiazole-4-carboxylic acid ethyl ester's is synthetic
40g m-anisidine is joined in 800ml ethyl acetate, add again 50ml pyridine, be cooled to 0 ℃, be added dropwise to 125g ethyl 2-(8-(chloroformyl)-3, 4-dihydro-isoquinoline-2 (1H)-yl)-5-iodine thiazole-4-carboxylic acid ethyl ester, keep system temperature to be no more than 10 ℃, after dropwising, 0 ℃ is continued to stir 14 hours, reaction solution is slowly poured in frozen water, add dilute hydrochloric acid, stir, separatory, collect organic phase, dry, after concentrated, upper silicagel column separates and obtains the iodo-2-of 132.3g ethyl-5-(8-(p-methylphenyl formamyl)-3, 4-dihydro-isoquinoline-2 (1H)-yl) thiazole-4-carboxylic acid ethyl ester.
H1-NMR(CDCl
3,400M):8.73(1H,brs),7.79～7.67(5H,m),7.35～7.26(2H,m),7.15(1H,m),4.23～4.11(4H,m),3.78(3H,s),3.46(2H,t),2.67(2H,t),1.32(3H,t)。
(7) the iodo-2-of ethyl-5-(8-(m-chloro phenyl amino formyl radical)-3,4-dihydro-isoquinoline-2 (1H)-yl) thiazole-4-carboxylic acid ethyl ester's is synthetic
42g m-chloro aniline is joined in 800ml ethyl acetate, add again 50ml pyridine, be cooled to 0 ℃, be added dropwise to 125g ethyl 2-(8-(chloroformyl)-3, 4-dihydro-isoquinoline-2 (1H)-yl)-5-iodine thiazole-4-carboxylic acid ethyl ester, keep system temperature to be no more than 10 ℃, after dropwising, 0 ℃ is continued to stir 14 hours, reaction solution is slowly poured in frozen water, add dilute hydrochloric acid, stir, separatory, collect organic phase, dry, after concentrated, upper silicagel column separates and obtains the iodo-2-of 124.1g ethyl-5-(8-(p-methylphenyl formamyl)-3, 4-dihydro-isoquinoline-2 (1H)-yl) thiazole-4-carboxylic acid ethyl ester.
H1-NMR(CDCl
3,400M):8.70(1H,brs),7.72～7.61(5H,m),7.32～7.24(2H,m),7.10(1H,m),4.20～4.05(4H,m),3.41(2H,t),2.62(2H,t),1.19(3H,t)。
Claims (6)
1. prepare a method for tetrahydro isoquinoline derivative, it is characterized in that benzyl-1 with 2-, 2,3,4-tetrahydroisoquinoline-8-carboxylic acid is starting raw material, is prepared into target product 5 through de-benzyl, replacement, acidylate, condensation four-step reaction, and synthetic route is as follows.
2. according to the method for claim 1,4 steps described in it is characterized by are reacted and are,
(1), with 2-benzyl-1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid (1) is starting raw material, takes off benzyl obtain 2 with debenzylation reagent;
(2) under alkaline condition, there is nucleophilic substitution reaction with the chloro-5-iodine of 2-4-thiazolecarboxylic acid ethyl ester 2, obtain 3;
(3) react and obtain 4 with chloride reagent 3;
(4) carry out condensation reaction 4 with corresponding substituted aniline, obtain 5.
Wherein, A is C
1-6alkyl, C
1-6alkoxyl group, hydrogen, halogen, cyano group, nitro.
3. according to the method for claim 1-2, it is characterized in that, described preparation 1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid debenzylation reagent used is selected from one or more the mixture in palladium carbon-hydrogen, palladium carbon-ammonium formiate, palladium hydroxide-hydrogen, liquefied ammonia; Described nucleophilic substitution reaction alkali used is selected from one or more the mixture in sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, salt of wormwood, triethylamine, sodium bicarbonate, pyridine, triisopropylamine, saleratus; Described acyl chloride reaction acylating reagent used is selected from one or more the mixture in sulfur oxychloride, oxalyl chloride, phosphorus oxychloride, phosphorus pentachloride; Described condensation reaction alkali used is selected from one or more the mixture in sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, salt of wormwood, triethylamine, sodium bicarbonate, pyridine, triisopropylamine, saleratus.
4. according to the method for claim 1-2, it is characterized in that, described preparation 1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid solvent used is selected from one or more the mixture in methyl alcohol, ethanol, n-propyl alcohol, Virahol; Described nucleophilic substitution reaction solvent used is selected from one or more the mixture in tetrahydrofuran (THF), toluene, o-Xylol, p-Xylol, m-xylene, DMF, N,N-dimethylacetamide; Described acyl chloride reaction solvent used is selected from one or more the mixture in sulfur oxychloride, oxalyl chloride; Described condensation reaction solvent used is selected from one or more the mixture in methylene dichloride, trichloromethane, ethyl acetate, tetrahydrofuran (THF), toluene.
5. according to the method for claim 1-2, it is characterized in that, described preparation 1,2,3, the temperature of reaction of 4-tetrahydroisoquinoline-8-carboxylic acid is 0 ℃～60 ℃; The temperature of reaction of described nucleophilic substitution reaction is the reflux temperature of 0 ℃-solvent; The temperature of reaction of described acyl chloride reaction is the reflux temperature of 0 ℃-solvent; The temperature of reaction of described condensation reaction is the reflux temperature of 0 ℃-solvent.
6. according to the method for claim 1-2, it is characterized in that, described preparation 1,2,3, the temperature of reaction of 4-tetrahydroisoquinoline-8-carboxylic acid is room temperature; The temperature of reaction of described nucleophilic substitution reaction is the reflux temperature of solvent; The temperature of reaction of described acyl chloride reaction is 0 ℃; The temperature of reaction of described condensation reaction is the reflux temperature of solvent.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107778231A (en) * | 2016-08-30 | 2018-03-09 | 湖南华腾制药有限公司 | A kind of preparation method of tetrahydro isoquinoline derivative |
| CN112679469A (en) * | 2020-12-29 | 2021-04-20 | 武城县人民医院 | Tetrahydroisoquinoline derivatives, preparation method and application |
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| CN1617856A (en) * | 2001-12-05 | 2005-05-18 | 安万特医药德国有限公司 | Substituted 4-phenyltetrahydroisoquinolinium, process for their preparation, their use as a medicament, and medicament containing them |
| CN101360743A (en) * | 2006-01-30 | 2009-02-04 | Irm责任有限公司 | Polycyclic 1,2,3, 4-tetrahydro-isoquinoline derivatives and compositions containing them as PPAR modulators |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1617856A (en) * | 2001-12-05 | 2005-05-18 | 安万特医药德国有限公司 | Substituted 4-phenyltetrahydroisoquinolinium, process for their preparation, their use as a medicament, and medicament containing them |
| CN101360743A (en) * | 2006-01-30 | 2009-02-04 | Irm责任有限公司 | Polycyclic 1,2,3, 4-tetrahydro-isoquinoline derivatives and compositions containing them as PPAR modulators |
Non-Patent Citations (2)
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| ALLA ZABLOTSKAYA,ET AL: "Synthesis, physicochemical characterization, cytotoxicity,antimicrobial, anti-inflammatory and psychotropic activity of new N-[1,3-(benzo)thiazol-2-yl]-u-[3,4-dihydroisoquinolin-2(1H)-yl] alkanamides", 《EUROPEAN JOURNAL OF MEDICICAL CHEMISTRY》, vol. 70, 16 October 2013 (2013-10-16), pages 846 - 856 * |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107778231A (en) * | 2016-08-30 | 2018-03-09 | 湖南华腾制药有限公司 | A kind of preparation method of tetrahydro isoquinoline derivative |
| CN112679469A (en) * | 2020-12-29 | 2021-04-20 | 武城县人民医院 | Tetrahydroisoquinoline derivatives, preparation method and application |
| CN112679469B (en) * | 2020-12-29 | 2021-11-16 | 山东研峰新材料科技有限公司 | Tetrahydroisoquinoline derivatives, preparation method and application |
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Application publication date: 20140514 |