CN101250157A - Method for synthesizing 2-substituted-3,4-dihydro-1-isoquinoline ketones and use thereof for preparing cardiovascular agents - Google Patents
Method for synthesizing 2-substituted-3,4-dihydro-1-isoquinoline ketones and use thereof for preparing cardiovascular agents Download PDFInfo
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Abstract
The invention discloses a synthesis method of 2-substituted-3, 4-dihyidro-1-isoquinoline ketone compound and a relative application in the drug preparation for cardiovascular disease, wherein the compound is represented as above, R1 is gaseous normal alkyl and aromatic group or various substituted alkyl and aromatic group of C1-C19, R2 is OH, OCH3, CH3, NO2 and halogen or the like and can be one or more substituents. The preparation of 2-substituted-3, 4-dihyidro-1-isoquinoline ketone compound uses isovanillic acid ester as raw material, via six-step reaction as allyl etherified, Claisen rearrangement, oxidation, reaction with primary amine (generating Schiff base), reduction and aminolysis of molecular lactone, to synthesize the product. The isolated arterial ring tension test proves that the compound can relax vessel effectively. The 2-substituted-3, 4-dihyidro-1-isoquinoline ketone compound is a new potential cardiovascular drug, with wide application for preparing the drug of cardiovascular disease.
Description
Technical field
The invention discloses a kind of 2-and replace-3, the purposes of 4-dihydro-1-isobioquin group synthetic method and preparation treatment cardiovascular disease medicine preparation thereof with tangible vasodilatory effect.
Technical background
Along with the raising of people's living standard and the aging of population, cardiovascular disorder, particularly hypertensive sickness rate increases day by day.Data shows according to statistics, and China 35 is to 74 years old crowd, and hypertensive sickness rate is up to about 27%, and patient's number is near 100,013,000, and is annual newly-increased more than 3,000,000.Hypertension has become the modal cardiovascular disorder in the world, also is one of maximum prevailing disease, often causes the complication of internal organs such as the heart, brain, kidney, and human beings'health in serious harm.The medicine of the vasodilation of clinical application is all followed untoward reaction as nitrate esters, dihydropyridines and β-suprarenal gland energy retarding agent etc.
3 of bibliographical information, the synthetic method of 4-dihydro-1-isoquinolines has following several: be raw material with 4-hydroxyl-1-indone 1), under the trichoroacetic acid(TCA) effect, carry out the synthetic 5-hydroxyl-3 of Schmidt rearrangement reaction with sodium azide, 4-dihydro-1-isoquinolines, but yield has only 16%[Miyake, Yoshinori, et al.Journal of Labelled Compounds ﹠amp; Radiopharmaceuticals, 2000,43 (10): 983～988].2) with isoquinoline 99.9 be starting raw material, get isoquinoline-5-sulfonic acid through salify, sulfonation, then with fused sodium hydroxide and potassium hydroxide react 1,5-dihydroxyl isoquinoline 99.9 is that catalyst reduction obtains 5-hydroxyl-3 at last with 5%Pd/C, 4-dihydro-1-isoquinolines, total recovery 47.6%[appoints eyebrow .5-hydroxyls-3 such as Zhang Rui, 4-dihydro-1-isoquinolines synthetic. synthetic chemistry, 2006,14 (5): 532～533].3) the carbamate method synthesizes 3,4-dihydro-1-isoquinolinone derivatives (Gary L.Grunewald, et al, J.Med.Chem.1999,42,4351-4361; Xiao-jun Wang, et a1, TetrahedronLetters, 1998,39,6609-6612).4) carbonylation reaction of the catalytic phenylethylamine compounds of palladium [Kazuhiko Orito, et al, J.Am.Chem.Soc.2004,126 (44), 14342-14343].5) other method (Atanas P.Venkov, et al, Tetrahedron, 1996,52,1451-1460).
Summary of the invention
The 2-that is to provide a class to have vasodilator, brings high blood pressure down, treats cardiovascular disorder of the present invention day replaces-3, the purposes of 4-dihydro-1-isobioquin group synthetic method and preparation cardiovascular agent thereof.
For achieving the above object, the preparation method that the present invention adopts is as follows:
1) at first when alkaline reagents exists, 3-hydroxybenzoate class and allyl halide refluxed in organic solvent makes 3-allyloxy benzoic ether; Described 3-hydroxybenzoate is 3-methyl hydroxybenzoate, ethyl ester, propyl ester or isopropyl ester; Methyl esters, ethyl ester, propyl ester or the isopropyl ester of isovanillic acid (3-hydroxyl-4-methoxybenzoic acid); Or there is substituent 3-hydroxybenzoate other position of phenyl ring; Used alkaline reagents is yellow soda ash, salt of wormwood, sodium hydroxide or potassium hydroxide, and wherein the mol ratio of alkaline reagents and 3-hydroxybenzoate class is 1: 1～1: 4; Allyl halide is chlorallylene, allyl bromide 98, allyl iodide or 3-methyl-2-butene-1-bromine; The mol ratio of allyl halide and 3-hydroxybenzoate class is 1: 1～1: 2; Organic solvent is acetone, tetrahydrofuran (THF), ethyl acetate, methyl alcohol or ethanol; Every mole of 3-hydroxybenzoate class adds organic solvent 2～5L.
2) secondly, 3-allyloxy benzoic ether is heated to 150～220 ℃ or 3-allyloxy benzoic ether refluxed at high boiling organic solvent Claisen takes place reset and generate 2-allyl group-3-hydroxybenzoate class; Used organic solvent is N, accelerine, N, N-Diethyl Aniline or N,N-dimethylacetamide; Every mole of 3-allyloxy benzoic ether adds high boiling organic solvent 1～3L.
3) then, 2-allyl group-3-hydroxybenzoate class is dissolved in acetone, water, the trimethyl carbinol or three's the mixed solvent, adds oxygenant again or feed ozone at-30～-80 ℃, reaction generates 2-oxygen acetylbenzoic acid ester class; Wherein every mole of 2-allyl group-3-hydroxybenzoate class adds solvent 5～10L; Said oxygenant is perosmic anhydride/sodium periodate, and the mol ratio of oxygenant and 2-allyl group-3-hydroxybenzoate class is 0.01～0.3: 1.
4) last, 2-oxygen acetylbenzoic acid ester class and primary amine reaction generate Schiff alkali intermediate, obtain secondary amine with the reductive agent reduction again, and the aminolysis that the latter carries out the molecule lactone can obtain 2-replacement-3,4-dihydro-1-isobioquin group.The mol ratio of 2-oxygen acetylbenzoic acid ester class and primary amine is 1: 1～1: 2 in the reaction; Used reductive agent is sodium borohydride or sodium triacetoxy borohydride, and the mol ratio of reductive agent and 2-oxygen acetylbenzoic acid ester class is 4: 1～1: 1; Used primary amine is the Armeen of various replacements, is reflected between 0～50 ℃ to carry out.
When primary amine is the aromatic amine of aromatic amine or replacement, isolate intermediate secondary amine by crystallization or chromatography, the aminolysis that carries out ester again under 100～200 ℃ can obtain 2-and replace-3,4-dihydro-1-isobioquin group; Or, obtain carboxylic acid earlier with carboxyester hydrolysis, and adding condensing agent again and obtain target compound, described condensing agent is DCC or DIC, its consumption is 1-4 a times of carboxylic acid molar weight.
Compound according to above synthetic method obtains is characterized in that: its general structure of described compound is as follows:
R in the formula
1=C
1-C
18Alkyl, the aromatic base of straight chained alkyl, aromatic base or various replacements; R
2=OH, OCH
3, CH
3, NO
2Or halogen, can 1 substituting group or a plurality of substituting group on the phenyl ring.
In order to verify that 2-of the present invention replaces-3, the 4-dihydro-vasodilatory effect of 1-compound of isobioquin group has carried out the vasodilator test to following compounds.
1, (R)-5-hydroxyl-6-methoxyl group-2-(1-phenylethyl)-3,4-dihydro-1-isoquinolines
2,5-hydroxyl-6-methoxyl group-2-benzyl-3,4-dihydro-1-isoquinolines
3,5-hydroxyl-6-methoxyl group-2-[2-(1-morpholinyl) ethyl]-3,4-dihydro-1-isoquinolines
4, (S)-5-hydroxyl-6-methoxyl group-2-(1-benzyl-2-oxyethyl group-2-oxygen ethyl)-3,4-dihydro-1-isoquinolines
5,5-hydroxyl-6-methoxyl group-2-(2-diethylin ethyl)-3,4-dihydro-1-isoquinolines
6,5-hydroxyl-6-methoxyl group-2-[2-(piperidino) ethyl]-3,4-dihydro-1-isoquinolines
7,5-hydroxyl-6-methoxyl group-2-(3-chloro-4-fluorophenyl)-3,4-dihydro-1-isoquinolines
8,5-hydroxyl-6-methoxyl group-2-ethyl-3,4-dihydro-1-isoquinolines
9,5-hydroxyl-6-methoxyl group-2-(2-oxyethyl group-2-oxygen ethyl)-3,4-dihydro-1-isoquinolines
10,5-hydroxyl-6-methoxyl group-2-hexadecyl-3,4-dihydro-1-isoquinolines
11,5-hydroxyl-6-methoxyl group-2-(4-aminomethyl phenyl)-3,4-dihydro-1-isoquinolines
12,5-hydroxyl-6-methoxyl group-2-phenyl-3,4-dihydro-1-isoquinolines
13,7-hydroxyl-6-methoxyl group-2-benzyl-3,4-dihydro-1-isoquinolines
14,7-hydroxyl-6-methoxyl group-2-[2-(1-morpholinyl) ethyl]-3,4-dihydro-1-isoquinolines
One, synthetic compound is to the relexation of rat coronary artery
Get the DA rat, sacrificed by decapitation is taken out heart, and microscopically separates coronary artery, immerses in the cold Krebs liquid, and coronary artery is cut into the long annulus section of 1mm.The vascular circle of handling well is enclosed within on the steel wire of two 60 μ m, one of them connects tonotransducer, and another connects micromatic setting (regulating load tension force).Install the back by bridging amplifier, antiotasis is shown in computer screen.Arterial ring is inserted 37 ℃ of Myograph thermostatic baths that contain Krebs liquid 5mL, and lasting feeding contains 95%O
2And 5%CO
2Mixed gas, pH keeps 7.4.Before the experiment, arterial ring tranquillization load 2mN, every 15min changes liquid 1 time, stablizes 1.5h.With K
+-Krebs liquid (contains K
+60mmolL
-1) check arterial ring shrinkability, twice shrinkage amplitude differs less than 10% and is used for experiment.Write down 60mmolL earlier
-1K
+The contraction that causes, steadily the back adds different given the test agent.Calculate diastolic rate with [shrinkage amplitude before (shrinkage amplitude before the medicine-medicine post shrinkage amplitude)/medicine] * 100%.The results are shown in Table 1.
Table 1. synthetic compound is to the diastole effect of rat coronary artery
| Compound number | Concentration mol/L | 60mmol/L K +Shrinkage amplitude (mN) | Diastole amplitude (mN) behind the medicine | Diastolic rate (%) |
| 1 | 10 -4 | 2.89 | -2.66 | 92 |
| 2 | 10 -4 | 1.23 | -1.01 | 82 |
| 3 | 10 -4 | 1.08 | -0.30 | 28 |
| 4 | 10 -4 | 2.60 | -2.44 | 94 |
| 4 | 10 -5 | 1.34 | -1.03 | 77 |
| 5 | 10 -4 | 1.16 | -0.50 | 43 |
| 6 | 10 -4 | 1.22 | -0.17 | 14 |
The result shows, No. 1, sample, and the diastolic rate of No. 2 and No. 4 is respectively 92%, 82% and 94%, shows that it has tangible diastole effect to coronary artery.And the diastolic rate of sample No. 3, No. 5 and No. 6 is lower than 50%.
Two, to the relexation of mouse aorta abdominalis
Get the ICR mouse, dislocation is put to death, and separates aorta abdominalis, immerses in the cold Krebs liquid, and artery is cut into the long annulus section of 1mm.The vascular circle of handling well is enclosed within on two draw points, and method is the same.Write down 60mmolL earlier
-1K
+The contraction that causes, steadily the back adds the different given the test agent of different concns.Calculate diastolic rate with [shrinkage amplitude before (shrinkage amplitude before the medicine-medicine post shrinkage amplitude)/medicine] * 100%.Test-results sees Table 2.The result shows, the diastolic rate of compound No. 4, No. 6, No. 11 and No. 13 is respectively and has surpassed 50%, shows that its aorta to mouse has tangible diastole effect.
Table 2. synthetic compound is to the diastole effect of mouse aorta abdominalis artery
| Compound number | Concentration mol/L | 60mmol/L K +Shrinkage amplitude (mN) | Diastole amplitude (mN) behind the medicine | Diastolic rate (%) |
| 1 | 10 -4 | 3.44 | -1.24 | 35.88 |
| 2 | 10 -4 | 3.23 | -1.32 | 40.84 |
| 3 | 10 -4 | 3.21 | -0.43 | 13.33 |
| 4 | 10 -4 | 3.03 | -2.26 | 74.57 |
| 5 | 10 -4 | 3.93 | -0.96 | 24.46 |
| 6 | 10 -4 | 2.22 | -1.61 | 72.46 |
| 7 | 10 -4 | 8.21 | -1.15 | 14.41 |
| 8 | 10 -4 | 8.41 | -0.92 | 10.94 |
| 9 | 10 -4 | 8.37 | -3.93 | 46.90 |
| 10 | 10 -4 | 8.53 | -1.10 | 12.86 |
| 11 | 10 -4 | 6.8 | -5.08 | 74.80 |
| 12 | 10 -4 | 5.35 | -1.22 | 22.82 |
| 13 | 10 -4 | 9.65 | -7.42 | 76.88 |
| 14 | 10 -4 | 7.85 | -1.38 | 17.57 |
Three, to the relexation of artery on the rat mesentery
Get the DA rat, put to death, separate superior mesenteric artery, immerse in the cold Krebs liquid, microscopically is cut into the long annulus section of 1mm with artery.The same method, record 60mmolL earlier
-1K
+The contraction that causes, steadily the back adds the different given the test agent of different concns.Calculate diastolic rate with [shrinkage amplitude before (shrinkage amplitude before the medicine-medicine post shrinkage amplitude)/medicine] * 100%.The results are shown in Table 3.The result shows, the diastolic rate of No. 11, compound and No. 13 is respectively 85.6% and 91.5%, shows that its superior mesenteric artery to rat has tangible diastole effect.The diastolic rate 52.8% that No. 8, compound, and the diastolic rate of sample No. 7, No. 9, No. 10, No. 12 and No. 14 is lower than 50%.
Table 3. synthetic compound is to the diastole effect of rat mesenteric artery
| The synthetic compound numbering | The different concns synthetic compound is to the diastolic rate (%) of blood vessel | ||
| 10 -6mol/L | 10 -5mo/L | 10 -4mol/L | |
| 7 | 3.8 | 8.8 | 41.3 |
| 8 | 10.1 | 22.9 | 52.8 |
| 9 | 3.3 | 5.8 | 43.5 |
| 10 | 1.1 | 3.2 | 6.4 |
| 11 | 8.1 | 12.0 | 85.6 |
| 12 | 4.5 | 9.5 | 43.4 |
| 13 | 9.2 | 22.2 | 91.5 |
| 14 | 3.9 | 7.7 | 15.8 |
The 2-that the present invention relates to replaces-3, the application of the composition of 4-dihydro-1 (2H)-compound of isobioquin group in the preparation cardiovascular agent, and these application can be capsule, oral liquid or granule or injection.These preparations can be made according to the conventional preparation technology of various preparations, and wherein content of effective is 1-100mg, and preferred content is 5-30mg.
Can contain pharmaceutical excipient in the oral preparations that the present invention relates to, comprise additive, stablizer, solubilizing agent, lubricant etc., as glucose, lactose, Mierocrystalline cellulose, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, starch, pectin, cyclodextrin, soil temperature-80, polyvinyl alcohol, Magnesium Stearate, talcum powder etc.
Embodiment
The preparation of embodiment 1:3-allyloxy-4-methoxyl methyl benzoate
Get 2.0g (11mmol) isovanillic acid methyl esters in the 250ml round-bottomed flask, add 30ml acetone, 4.6g (33mmol) Anhydrous potassium carbonate adds 1.5ml (16.5mmol) allyl bromide 98, reflux 2h behind the stirring 30min under the room temperature.Be cooled to room temperature, filter, mother liquor pressure reducing and steaming acetone adds the 150ml ethyl acetate extraction.Use 2molL successively
-1Hydrochloric acid, saturated sodium bicarbonate solution, water and salt water washing.Organic phase with anhydrous sodium sulfate drying after the pressure reducing and steaming solvent, residue gets the 2.3g white crystal with ethyl alcohol recrystallization.Productive rate: 98%, mp:56.5～58.5 ℃.
1HNMR(300MHz，CDCl
3)，δ
H：7.62(d，1H，Ar-H)，7.39(s，1H，Ar-H)，6.82(d，1H，Ar-H)，6.15(m，1H，＝CH-)，5.33(d，2H，＝CH
2)，4.52(d，2H，-OCH
2-)，3.94(s，3H，-OCH
3)，3.82(s，3H，O-CH
3)。
The preparation of embodiment 2:2-allyl group-3-hydroxyl-4-methoxyl methyl benzoate
Get 2.0g (9mmol) 3-allyloxy-4-methoxyl methyl benzoate in the 100ml round-bottomed flask, add the new N of steaming, accelerine 10ml.In nitrogen protection, reaction mixture heated and stirred backflow 4h.Be cooled to room temperature, add 30ml 3molL
-1Hydrochloric acid, and the usefulness ethyl acetate extraction (3 * 40ml), merge organic phase, and use saturated sodium bicarbonate solution, water and salt water washing successively.Organic phase with anhydrous sodium sulfate drying after the pressure reducing and steaming solvent, residue separates through rapid column chromatography that (eluent: sherwood oil: ethyl acetate=5: 1), the ethyl acetate/petroleum ether crystallization gets the 1.8g colourless acicular crystal.Productive rate: 90%, mp:74.0～74.5 ℃.IR(cm
-1)：3455，1701，1602，1578。
1HNMR(300MHz，CDCl
3)，δ
H：7.52(d，1H，Ar-H)，6.75(d，1H，Ar-H)，6.00(m，1H，＝CH-)，5.81(s，1H，-OH)，4.98(d，2H，＝CH
2)，3.92(s，3H，OCH
3)，3.84(s，3H，-OCH
3)，3.83(d，2H，-CH
2-)。
The preparation of embodiment 3:2-oxygen ethyl-3-hydroxyl-4-methoxyl methyl benzoate
Get 1.8g (8mmol) compound 2-allyl group-3-hydroxyl-4-methoxyl methyl benzoate in the 250ml round-bottomed flask, add 48ml acetone, 16ml water, the 16ml trimethyl carbinol and 0.1g (0.4mmol) perosmic anhydride, lucifuge stirs 30min under the room temperature, add 4.2g (20mmol) sodium periodate, lucifuge stirs 4h under the room temperature.Diatomite filtration, the mother liquor pressure reducing and steaming acetone and the trimethyl carbinol add the 100ml ethyl acetate extraction.Use saturated sodium bisulfite, water and salt water washing successively.Organic phase with anhydrous sodium sulfate drying after the pressure reducing and steaming solvent, residue separates through rapid column chromatography that (eluent: sherwood oil: ethyl acetate=3: 1), the ethyl acetate/petroleum ether crystallization gets the 1.47g colourless acicular crystal.Productive rate: 82.1%, mp:127.0～128.5 ℃.IR(cm
-1)：3500，1716，1624，1510.
1HNMR(300MHz，CDCl
3)，δ
H：9.77(s，1H，-CHO)，7.62(d，1H，Ar-H)，6.83(d，1H，Ar-H)，3.94(s，3H，OCH
3)，3.82(s，3H，-OCH
3)，3.66(d，2H，-CH
2-)。
Embodiment 4:5-hydroxyl-6-methoxyl group-2-benzyl-3,4-dihydro-1-isoquinolines synthetic
Get 0.5g (2.2mmol) compound 2-oxygen ethyl-3-hydroxyl-4-methoxyl methyl benzoate in the 100ml round-bottomed flask, add 25ml 1, the 2-ethylene dichloride, 0.36ml (3.3mmol) benzylamine, stirring at room 30min, add 1.0g (4.4mmol) sodium triacetoxy borohydride, stirring at room 4h in batches.Filter, (eluent: chloroform: methyl alcohol=30: 1), the ethyl acetate/petroleum ether crystallization gets the colourless tabular crystal of 0.47g through the rapid column chromatography separation.Productive rate: 76%, mp:96.5～97.5 ℃.IR(cm
-1)：3176，1634，1603，1574。
1HNMR(300MHz，CDCl
3)，δ
H：7.75(d，1H，Ar-H)，7.32(s，5H，Ar-H)，6.85(d，1H，Ar-H)，4.78(s，2H，-CH
2-Ph)，3.93(s，3H，-OCH
3)，3.46(t，2H，N-CH
2-)，2.94(t，2H，-CH
2-Ar)。
Embodiment 5:5-hydroxyl-6-methoxyl group-2-ethyl-3,4-dihydro-1-isoquinolines synthetic
With embodiment 4.Ethanolic soln with ethamine replaces benzylamine to get 5-hydroxyl-6-methoxyl group-2-ethyl-3,4-dihydro-1-isoquinolines.Productive rate: 70%.
Embodiment 6:5-hydroxyl-6-methoxyl group-2-hexadecyl-3,4-dihydro-1-isoquinolines synthetic
With embodiment 4.Replace benzylamine to get 5-hydroxyl-6-methoxyl group-2-hexadecyl-3,4-dihydro-1-isoquinolines with cetylamine.Productive rate: 69%.
Embodiment 7:(R)-and 5-hydroxyl-6-methoxyl group-2-(1-phenyl) ethyl-3,4-dihydro-1-isoquinolines synthetic
With embodiment 4.Replace benzylamine to get (R)-5-hydroxyl-6-methoxyl group-2-(1-phenyl) ethyl-3,4-dihydro-1-isoquinolines with (R)-1-phenyl-ethyl amine.Productive rate: 74%.
Embodiment 8:(S)-and 5-hydroxyl-6-methoxyl group-2-(1-benzyl-2-oxyethyl group)-2-oxygen ethyl-3,4-dihydro-1-isoquinolines synthetic
With embodiment 4.Replace benzylamine to get (S)-5-hydroxyl-6-methoxyl group-2-(1-benzyl-2-oxyethyl group)-2-oxygen ethyl-3,4-dihydro-1-isoquinolines with (S)-phenylalanine ethyl ester.Productive rate: 71%.
Embodiment 9:5-hydroxyl-6-methoxyl group-2-(2-oxyethyl group)-2-oxygen ethyl-3,4-dihydro-1-isoquinolines synthetic
With embodiment 4.Replace benzylamine to get 5-hydroxyl-6-methoxyl group-2-(2-oxyethyl group)-2-oxygen ethyl-3,4-dihydro-1-isoquinolines with glycine ethyl ester.Productive rate: 68%.
Embodiment 10:5-hydroxyl-6-methoxyl group-2-(2-diethylin) ethyl-3,4-dihydro-1-isoquinolines synthetic
With embodiment 4.Replace benzylamine to get 5-hydroxyl-6-methoxyl group-2-(2-diethylin) ethyl-3,4-dihydro-1-isoquinolines with 2-diethylin ethamine.Productive rate: 66%.
Embodiment 11:5-hydroxyl-6-methoxyl group-2-[2-(piperidino)] ethyl-3,4-dihydro-1-isoquinolines synthetic
With embodiment 4.Replace benzylamine to get 5-hydroxyl-6-methoxyl group-2-[2-(piperidino) with 2-(piperidino) ethamine] ethyl-3,4-dihydro-1-isoquinolines.Productive rate: 68%.
Embodiment 12:5-hydroxyl-6-methoxyl group-2-[2-(1-morpholinyl)] ethyl-3,4-dihydro-1-isoquinolines synthetic
With embodiment 4.Replace benzylamine to get 5-hydroxyl-6-methoxyl group-2-[2-(1-morpholinyl) with 2-(1-morpholinyl) ethamine] ethyl-3,4-dihydro-1-isoquinolines.Productive rate: 68%.
Embodiment 13:5-hydroxyl-6-methoxyl group-2-phenyl-3,4-dihydro-1-isoquinolines synthetic
Get 0.5g (2.2mmol) 2-oxygen ethyl-3-hydroxyl-4-methoxyl methyl benzoate in the 100ml round-bottomed flask, add 25ml 1, the 2-ethylene dichloride, 0.36ml (3.3mmol) aniline, stirring at room 30min adds 1.0g (4.4mmol) sodium borohydride, stirring at room 4h in batches.Filter, separate (eluent: chloroform: methyl alcohol=30: 1-20: 1), get product 0.43g through rapid column chromatography.In this product, add 20mL toluene, reflux 24h.Remove toluene, product through separate through rapid column chromatography colourless tabular crystal.Productive rate: 46%.
Embodiment 14:5-hydroxyl-6-methoxyl group-2-(4-methyl) phenyl-3,4-dihydro-1-isoquinolines synthetic
With embodiment 13.Replace aniline to obtain 5-hydroxyl-6-methoxyl group-2-(4-methyl) phenyl-3,4-dihydro-1-isoquinolines with the 4-monomethylaniline.Productive rate: 49%.
Embodiment 15:5-hydroxyl-6-methoxyl group-2-(3-chloro-4-fluorine) phenyl-3,4-dihydro-1-isoquinolines synthetic
With embodiment 13.Replace aniline to obtain 5-hydroxyl-6-methoxyl group-2-(3-chloro-4-fluorine) phenyl-3,4-dihydro-1-isoquinolines with 3-chloro-4-fluoroaniline.Productive rate: 43%.
The preparation of embodiment 16:3-O-(3-methyl-2-butene base)-4-methoxyl methyl benzoate
With embodiment 1.Obtain 3-O-(3-methyl-2-butene base)-4-methoxyl methyl benzoate with 3-methyl-2-butene base-1-bromo for allyl bromide 98.Productive rate 95%.
The preparation of embodiment 17:2-(3-methyl-2-butene base)-4-methoxyl group-5 methyl hydroxybenzoate
With embodiment 2.Productive rate 70%.mp：74.0-75.0℃。
The preparation of embodiment 18:2-oxygen ethyl-4-methoxyl group-5-methyl hydroxybenzoate
With embodiment 3.Productive rate 36%.
Embodiment 19:7-hydroxyl-6-methoxyl group-2-benzyl-3,4-dihydro-1-isoquinolines synthetic
With embodiment 4.Replace 2-oxygen ethyl-3-hydroxyl-4-methoxyl methyl benzoate to obtain 7-hydroxyl-6-methoxyl group-2-benzyl-3,4-dihydro-1-isoquinolines with 2-oxygen ethyl-4-methoxyl group-5-hydroxy-benzoic acid methyl esters.Productive rate: 66.5%.mp：190.0-191.0℃。
1HNMR(300MHz，CDCl
3)，δ
H：7.74(s，1H，Ar-H)，7.30(m，5H，Ar-H)，6.60(s，1H，Ar-H)，4.77(s，2H，-CH
2-Ph)，3.92(s，3H，-OCH
3)，3.45(t，2H，N-CH
2-)，2.85(t，2H，-CH
2-Ar)。
Embodiment 20:7-hydroxyl-6-methoxyl group-2-[2-(1-morpholinyl) ethyl]-3,4-dihydro-1-isoquinolines
With embodiment 12.Replace 2-oxygen ethyl-3-hydroxyl-4-methoxyl methyl benzoate to obtain 7-hydroxyl-6-methoxyl group-2-[2-(1-morpholinyl) ethyl with 2-oxygen ethyl-4-methoxyl group-5-hydroxy-benzoic acid methyl esters]-3,4-dihydro-1-isoquinolines.Yield 68.3%.
What more than provide only is several embodiment of the present invention, and the present invention is not limited to above embodiment.
Claims (3)
1,2-replaces-3, and 4-dihydro-1-isobioquin group synthetic method is characterized in that:
1) at first when alkaline reagents exists, 3-hydroxybenzoate class and allyl halide refluxed in organic solvent makes 3-allyloxy benzoic ether; Described 3-hydroxybenzoate is 3-methyl hydroxybenzoate, ethyl ester, propyl ester or isopropyl ester; Methyl esters, ethyl ester, propyl ester or the isopropyl ester of isovanillic acid (3-hydroxyl-4-methoxybenzoic acid); Or there is substituent 3-hydroxybenzoate other position of phenyl ring; Used alkaline reagents is yellow soda ash, salt of wormwood, sodium hydroxide or potassium hydroxide, and wherein the mol ratio of alkaline reagents and 3-hydroxybenzoate class is 1: 1～1: 4; Allyl halide is chlorallylene, allyl bromide 98, allyl iodide or 3-methyl-2-butene-1-bromine; The mol ratio of allyl halide and 3-hydroxybenzoate class is 1: 1～1: 2; Organic solvent is acetone, tetrahydrofuran (THF), ethyl acetate, methyl alcohol or ethanol; Every mole of 3-hydroxybenzoate class adds organic solvent 2～5L.
2) secondly, 3-allyloxy benzoic ether is heated to 150～220 ℃ or 3-allyloxy benzoic ether refluxed at high boiling organic solvent Claisen takes place reset and generate 2-allyl group-3-hydroxybenzoate class; Used organic solvent is N, accelerine, N, N-Diethyl Aniline or N,N-dimethylacetamide; Every mole of 3-allyloxy benzoic ether adds high boiling organic solvent 1～3L.
3) then, 2-allyl group-3-hydroxybenzoate class is dissolved in acetone, water, the trimethyl carbinol or three's the mixed solvent, adds oxygenant again or feed ozone at-30～-80 ℃, reaction generates 2-oxygen acetylbenzoic acid ester class; Wherein every mole of 2-allyl group-3-hydroxybenzoate class adds solvent 5～10L; Said oxygenant is perosmic anhydride/sodium periodate, and the mol ratio of oxygenant and 2-allyl group-3-hydroxybenzoate class is 0.01～0.3: 1.
4) last, 2-oxygen acetylbenzoic acid ester class and primary amine reaction generate Schiff alkali intermediate, obtain secondary amine with the reductive agent reduction again, and the aminolysis that the latter carries out the molecule lactone can obtain 2-replacement-3,4-dihydro-1-isobioquin group.The mol ratio of 2-oxygen acetylbenzoic acid ester class and primary amine is 1: 1～1: 2 in the reaction; Used reductive agent is sodium borohydride or sodium triacetoxy borohydride, and the mol ratio of reductive agent and 2-oxygen acetylbenzoic acid ester class is 4: 1～1: 1; Used primary amine is the Armeen of various replacements, is reflected between 0～50 ℃ to carry out.
When primary amine is the aromatic amine of aromatic amine or replacement, isolate intermediate secondary amine by crystallization or chromatography, the aminolysis that carries out ester again under 100～200 ℃ can obtain 2-and replace-3,4-dihydro-1-isobioquin group; Or, obtain carboxylic acid earlier with carboxyester hydrolysis, and adding condensing agent again and obtain 2-replacement-3,4-dihydro-1-isobioquin group, described condensing agent are DCC or DIC, its consumption is 1-4 a times of carboxylic acid molar weight.
2,2-according to claim 1 replaces-3, the compound that the 4-dihydro-1-isobioquin group synthetic method obtains, and it is characterized in that: its general structure of described compound is as follows:
R in the formula
1=C
1-C
18Alkyl, the aromatic base of straight chained alkyl, aromatic base or various replacements; R
2=OH, OCH
3, CH
3, NO
2Or halogen, can 1 substituting group or a plurality of substituting group on the phenyl ring.
3,2-according to claim 1 and 2 replaces-3, and 4-dihydro-1-compound of isobioquin group is characterized in that: this compounds of synthetic has tangible vasodilatory activity, has the purposes of preparation treatment cardiovascular disease medicine preparation.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102503781A (en) * | 2011-09-28 | 2012-06-20 | 河北工业大学 | Method for preparing phenol ether through reaction of phenolic compound and halogenated hydrocarbon |
| CN102633717A (en) * | 2012-03-30 | 2012-08-15 | 西南大学 | N-acetyl-quinoline-2 (1H) ketone compounds as well as preparation method and application thereof |
| CN105198810A (en) * | 2015-07-16 | 2015-12-30 | 西安交通大学 | 2-benzyl-1-isoquinolone compound as well as synthesis method and application thereof |
| CN109293480A (en) * | 2018-10-31 | 2019-02-01 | 陕西硕博电子材料有限公司 | Diallyl bisphenol, preparation method and Bismaleimides resin pre-polymer |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2639718A1 (en) * | 1976-09-03 | 1978-03-16 | Thomae Gmbh Dr K | NEW PHENYLAETHYLAMINE |
| US5731324A (en) * | 1993-07-22 | 1998-03-24 | Eli Lilly And Company | Glycoprotein IIb/IIIa antagonists |
| US6469026B2 (en) * | 2000-03-24 | 2002-10-22 | Millennium Pharmaceuticals, Inc. | Isoquinolone inhibitors of factor Xa |
| US7144894B2 (en) * | 2004-09-23 | 2006-12-05 | Bristol-Myers Squibb Company | Sulfonamide bicyclic compounds |
| TW200728277A (en) * | 2005-06-29 | 2007-08-01 | Palau Pharma Sa | Bicyclic derivatives as P38 inhibitors |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102503781A (en) * | 2011-09-28 | 2012-06-20 | 河北工业大学 | Method for preparing phenol ether through reaction of phenolic compound and halogenated hydrocarbon |
| CN102633717A (en) * | 2012-03-30 | 2012-08-15 | 西南大学 | N-acetyl-quinoline-2 (1H) ketone compounds as well as preparation method and application thereof |
| CN105198810A (en) * | 2015-07-16 | 2015-12-30 | 西安交通大学 | 2-benzyl-1-isoquinolone compound as well as synthesis method and application thereof |
| CN105198810B (en) * | 2015-07-16 | 2018-01-05 | 西安交通大学 | The compound of isobioquin group of 2 benzyl 1 and its preparation method and use |
| CN109293480A (en) * | 2018-10-31 | 2019-02-01 | 陕西硕博电子材料有限公司 | Diallyl bisphenol, preparation method and Bismaleimides resin pre-polymer |
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