CN102653542B - Synthetic method of narcotine - Google Patents
Synthetic method of narcotine Download PDFInfo
- Publication number
- CN102653542B CN102653542B CN201110049910.5A CN201110049910A CN102653542B CN 102653542 B CN102653542 B CN 102653542B CN 201110049910 A CN201110049910 A CN 201110049910A CN 102653542 B CN102653542 B CN 102653542B
- Authority
- CN
- China
- Prior art keywords
- methoxyl group
- dimethoxvbenzofuran
- methylene
- solvent
- ketone
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 0 CO*c1c(*)c(*(O)OC2C(*CCc3c4)c3c(*)c3*4OCO3)*2cc1 Chemical compound CO*c1c(*)c(*(O)OC2C(*CCc3c4)c3c(*)c3*4OCO3)*2cc1 0.000 description 2
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of medicines, relates to a synthetic method of narcotine and particularly relates to a synthetic method of narcotine by using an intermediate. The method comprises the following steps of: (1) carrying out bromination, hydrolysis, cyclization and condensation on vanillic aldehyde, and then reducing and salting to obtain 3-methoxyl-4,5-methylendioxyphenylethylamine hydrochloride; (2) carrying out cyclization, hydrolysis and halogenation on 2,3-dimethoxy benzoic acid to obtain 6,7-dimethoxybenzofuranone-3-acyl chloride; and (3) butting the 3-methoxyl-4,5-methylendioxyphenylethylamine hydrochloride with the 6,7-dimethoxybenzofuranone-3-acyl chloride to obtain N-beta-(3-methoxyl-4,5-methylendioxyphenyl)ethyl-6',7'-dimethoxybenzofuranone-3-acyl chloride, and then carrying out the cyclization, reduction, chiral resolution and methylation to obtain the narcotine. The preparation method disclosed by the invention overcomes the disadvantages of the existing synthetic method of the narcotine that the synthetic route is longer, the yield and the purity are low, the toxin of a used solvent is great, the solvent cannot be resolved, and the like. The preparation method has the advantages of low cost, suitableness for industrialization and the like.
Description
Technical field
The invention belongs to medical art, relate to the synthetic method of Noscapine, be specifically related to a kind of method utilizing intermediate to synthesize Noscapine.
background technology
Noscapine is the phthalic acid morphinane alkaloid of papaver opium, and pharmaceutical products is Noscapine hydrochloride (trade(brand)name: Codipect, Codipect).This product purposes is similar to Dextromethorphane Hbr, also have Papaverine sample bronchial smooth muscle spasmolysis, can suppress the cough that coughing centre and lung stretch reflwx cause, its antitussive effect is suitable with morphine monomethyl ether, feature is without analgesia, sedative effect, without floaty euphoria, without additive and tolerance, do not suppress to breathe and intestinal peristalsis, on the contrary, also have certain respiratory centre excitation, take the sustainable 4h of rear drug effect, be mainly used in pungency dry cough patient clinically.Noscapine is used as cough medicine in the past few decades always, oral administration, blood plasma peak concentration is reached after 1h, transformation period is 124min, absolute oral availability is 30%, major metabolite comprises cotarnine, hydrocotarnine and meconin, all comes from the fracture (as follows) of C-C key between isoquinoline 99.9 and 2-benzofuranone ring, and the ownership of its metabolite, bioavailability and pharmacokinetics have obtained more deep research all.
The internal metabolism of Noscapine
Noscapine (noscapine) is cumarone ketone group isoquinoline alkaloid:
Chemical name: ［ l-(R, S)-1-(1 '-(4 ', 5 '-dimethoxvbenzofuran ketone group))-2-methyl-8-methoxyl group-6,7-methylene-dioxy-1,2,3,4-tetrahydroisoquinoline
English name: ［ l-(R, S)-1-(1 '-(4 ', 5 '-dimethoxyphthalidyl))-2-methyl-8-
Methoxy-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline
CAS： 128-62-1
According to bibliographical information, the synthesis of Noscapine mainly contains two kinds of synthesis strategies: the first is by Bischler-Napieralski ring-closure reaction, synthesis isoquinoline 99.9 ring; Another kind of cotarnin(e) and the healthy and free from worry two portions of wheat dockings obtains product.Test the product obtained in document and be dl-Noscapine, also only have early stage once report about its fractionation, this fractionation work subsequently of also giving brings difficulty.In prior art, the synthetic route of Noscapine has a variety of, but all there is many deficiencies:
In route one, need to use a large amount of n-Butyl Lithium and lithium diisopropylamine, reaction conditions is comparatively harsh, not easily amplifies, the Noscapine DL body obtained, and through investigating the technique split, finds cannot split all the time.Therefore, this route is abandoned.
In route two, yield when piperonylaldehyde can not have been bought and dock is lower (22%), needs column chromatographic isolation and purification.In addition, end product can not split, and is unfavorable for suitability for industrialized production in this way.
In synthetic route three, yield very low (21-24%) during synthesis bromo-derivative, piperonylaldehyde can not be bought and end product can not split, and in addition, iodine is expensive, does not therefore also adopt the method.
In route four, generating with the time product-free of Hydrogen bromide demethylation, then attempting using BF3/ ether catalysis also not success, finally abandoning this route.
In synthetic route five, because the potassium cyanide used in reaction and methyl-sulfate are severe toxicity, cannot suitability for industrialized production, abandon this route.
In the synthetic method of above-mentioned Noscapine, equal Problems existing is that synthetic route is long; Or yield, purity are low; Or the solvent toxicity used is large, cannot split.In sum, in prior art, the cost compare of the synthetic method of Noscapine is high, brings very large inconvenience to its suitability for industrialized production.
summary of the invention
Technical problem to be solved by this invention is to provide a kind of synthetic method of new Noscapine, thus it is high to overcome the synthetic method cost existed in prior art, is not suitable for the shortcomings such as industrialization.
The present invention is achieved through the following technical solutions:
1. Vanillin obtains 3-methoxyl group-4-hydroxyl-5-bromobenzaldehyde (1) through bromo-reaction; 3-methoxyl group-4 is obtained again through hydrolysis reaction; 5-Dihydroxy benzaldehyde (2); 3-methoxyl group-4 is obtained again through ring-closure reaction; 5-methylene dioxo group benzaldehyde (3); 3-methoxyl group-4 is obtained through condensation reaction; 5-methylene-dioxy-beta-nitrostyrene (4); then 3-methoxyl group-4,5-methylene-dioxy phenethylamine hydrochloride (5) is obtained through reduction, salify;
2. 2,3-dimethoxybenzoic acids obtain 3-trichloromethyl-6,7-dimethoxvbenzofuran ketone (6) through ring-closure reaction, hydrolysis obtains 6 again, 7-dimethoxvbenzofuran ketone-3-carboxylic acid (7), then obtains 6,7-dimethoxvbenzofuran ketone-3-acyl chlorides (8) through halogenating reaction;
3. 3-methoxyl group-4, 5-methylene-dioxy phenethylamine hydrochloride (5) and 6, 7-dimethoxvbenzofuran ketone-3-acyl chlorides (8) docking obtains N-β-(3-methoxyl group-4, 5-methylenedioxyphenyl) ethyl-6', 7'-dimethoxvbenzofuran ketone-3-acid amides (9), (±)-1-[9-(3 ' is obtained again through ring-closure reaction, 4 '-dimethoxvbenzofuran ketone group)]-8-methoxyl group-6, 7-methylene-dioxy-3, 4-dihydro-isoquinoline (10), then (±)-E-1-[9-(3 ' is obtained through reduction reaction, 4 '-dimethoxvbenzofuran ketone group)]-8-methoxyl group-6, 7-methylene-dioxy-1, 2, 3, 4-tetrahydroisoquinoline (11), chiral fractionation obtains l-(R again, S)-1-[9-(3 ', 4 '-dimethoxvbenzofuran ketone group)]-8-methoxyl group-6, 7-methylene-dioxy-1, 2, 3, 4-tetrahydroisoquinoline (12), eventually pass methylation reaction and obtain Noscapine.
The concrete preparation method of Noscapine of the present invention is:
A. Vanillin is dissolved in protonic acid, drips bromine, obtain 3-methoxyl group-4-hydroxyl-5-bromobenzaldehyde (1) through bromo-reaction;
B. 3-methoxyl group-4-hydroxyl-5-bromobenzaldehyde (1) is hydrolyzed in the basic conditions and obtains 3-methoxyl group-4,5-Dihydroxy benzaldehyde (2);
C. 3-methoxyl group-4,5-Dihydroxy benzaldehyde (2) is in non-protonic solvent, adds mineral alkali, is obtained by reacting 3-methoxyl group-4,5-methylene dioxo group benzaldehyde (3) with cyclizing agent generation cyclization;
D. 3-methoxyl group-4,5-methylene dioxo group benzaldehyde (3) and Nitromethane 99Min. condensation obtain 3-methoxyl group-4,5-methylene-dioxies-beta-nitrostyrene (4);
E. 3-methoxyl group-4,5-methylene-dioxies-beta-nitrostyrene (4) obtains 3-methoxyl group-4,5-methylene-dioxy phenethylamine hydrochloride (5) through reduction, salify;
F. 2,3-dimethoxybenzoic acids obtain 3-trichloromethyl-6,7-dimethoxvbenzofuran ketone (6) with Chloral Hydrate cyclization under acid solvent condition;
G. 3-trichloromethyl-6,7-dimethoxvbenzofuran ketone (6) is hydrolyzed in the basic conditions and obtains 6,7-dimethoxvbenzofuran ketone-3-carboxylic acid (7);
H. 6,7-dimethoxvbenzofuran ketone-3-carboxylic acid (7) obtain 6,7-dimethoxvbenzofuran ketone-3-acyl chlorides (8) through halogenating reaction;
I. 3-methoxyl group-4,5-methylene-dioxy phenethylamine hydrochloride (5) and 6,7-dimethoxvbenzofuran ketone-3-acyl chlorides (8) docking obtains N-β-(3-methoxyl group-4,5-methylenedioxyphenyl) ethyl-6', 7'-dimethoxvbenzofuran ketone-3-acid amides (9);
J. N-β-(3-methoxyl group-4,5-methylenedioxyphenyl) ethyl-6', 7'-dimethoxvbenzofuran ketone-3-acid amides (9) obtains (±)-1-[9-(3 ' under the effect of cyclization reagent, 4 '-dimethoxvbenzofuran ketone group)]-8-methoxyl group-6,7-methylene-dioxy-3,4-dihydro-isoquinoline (10);
K. (±)-1-[9-(3 ', 4 '-dimethoxvbenzofuran ketone group)]-8-methoxyl group-6,7-methylene-dioxy-3,4-dihydro-isoquinoline (10) obtains (±)-E-1-[9-(3 ' through reduction reaction, 4 '-dimethoxvbenzofuran ketone group)]-8-methoxyl group-6,7-methylene-dioxy-1,2,3,4-tetrahydroisoquinoline (11);
L. (±)-E-1-[9-(3 ', 4 '-dimethoxvbenzofuran ketone group)]-8-methoxyl group-6,7-methylene-dioxy-1,2,3,4-tetrahydroisoquinoline (11) splits through chiral reagent and obtains l-(R, S)-1-[9-(3 ', 4 '-dimethoxvbenzofuran ketone group)]-8-methoxyl group-6,7-methylene-dioxy-1,2,3,4-tetrahydroisoquinoline (12);
M. l-(R, S)-1-[9-(3 ', 4 '-dimethoxvbenzofuran ketone group)]-8-methoxyl group-6,7-methylene-dioxy-1,2,3,4-tetrahydroisoquinoline (12) obtains target product Noscapine through methylation reaction;
Its reaction scheme is as follows:
Wherein, the protonic acid described in step a be in formic acid, acetic acid any one, preferred acetic acid, temperature of reaction is room temperature.
Solvent in step b is any one or its mixed solvent in ethanol, Virahol, water, preferably water; Alkali is selected from sodium carbonate, sodium hydroxide, potassium hydroxide, preferred sodium hydroxide, and temperature of reaction is reflux temperature.
Solvent described in step c be in DMF, dimethyl sulfoxide (DMSO) any one, cyclization reagent is methylene dichloride or methylene bromide, and temperature of reaction is reflux temperature.
Solvent in steps d be in formic acid, acetic acid any one, condensing agent is Nitromethane 99Min., and temperature of reaction is 80-120 DEG C.
Solvent in step e be in anhydrous diethyl ether, tetrahydrofuran (THF) any one, first-selected tetrahydrofuran (THF), reductive agent is lithium aluminium hydride or borine tetrahydrofuran (THF).
Acid solvent described in step f be in the vitriol oil, acetic acid any one, the first-selected vitriol oil, temperature of reaction is 20 DEG C-50 DEG C.
Solvent in step g be in ethanol, Virahol, water any one, or mixed solvent, first-selected water; Alkali is selected from sodium carbonate, sodium hydroxide, potassium hydroxide, first-selected sodium hydroxide, and temperature of reaction is reflux temperature.
Halogenating agent described in step h be in sulfur oxychloride, phosphorus oxychloride, phosphorus pentachloride any one, first-selected sulfur oxychloride.
Reagent in step I be in methylene dichloride, acetone any one, alkali is selected from sodium carbonate, salt of wormwood, first-selected salt of wormwood, and temperature of reaction is room temperature.
Solvent in step j be in toluene, glycol dimethyl ether any one, cyclization reagent is selected from phosphorus oxychloride, polyphosphoric acid, and temperature of reaction is reflux temperature.
Solvent in step k be in methyl alcohol, ethanol any one, go back original reagent and be selected from sodium borohydride, POTASSIUM BOROHYDRIDE, in sodium cyanoborohydride any one, first-selected sodium cyanoborohydride, temperature of reaction is room temperature.
Solvent in step l is any one or mix reagent in acetone, Virahol, water, and first-selected acetone-isopropanol mixed solvent, resolution reagent is tartrate, dibenzoyl tartaric acid, camphorsulfonic acid, first-selected dibenzoyl tartaric acid.
Methylating reagent described in step m is formaldehyde/formic acid, formaldehyde/sodium borohydride, methyl iodide, first-selected formaldehyde/formic acid, and temperature of reaction is reflux temperature.
It is long that this preparation method overcomes synthetic route in the existing synthetic method of Noscapine; Yield, purity are low; The solvent toxicity used is large, the shortcoming such as cannot to split.And it is low to have cost, be suitable for the advantages such as industrialization.
embodiment
Embodiment one:
3-methoxyl group
-4-hydroxyl
-5-bromobenzaldehyde
(1)preparation
In 1000 mL three-necked bottles, add 152 g Vanillins, 600 mL Glacial acetic acid, external cooling bath, careful dropping 168 g bromines, dropwise and continue stirring 12 h.Reaction solution is poured in 1800 mL frozen water, stir 0.5 h, suction filtration, washing, dry, obtain light yellow solid 218.5 g, yield: 95%.
Embodiment two:
3-methoxyl group
-4,5-dihydroxy benzaldehyde
(2)preparation
146 g sodium hydroxide are dissolved in 2200 mL water, add 1 g copper reduction, 1 g cupric oxide, add 144 g compounds in batches
(1), occur light yellow solid, be heated to backflow, solid fades away, back flow reaction 30 h.Cooling, external ice-water bath, drip concentrated hydrochloric acid and regulate pH=4, suction filtration, washing, extraction into ethyl acetate, saturated sodium-chloride washs, anhydrous sodium sulfate drying.Concentrated, recrystallization, obtains off-white color solid 69.5 g, yield: 66%.
Embodiment three:
3-methoxyl group
-4,5-methylene dioxo group benzaldehyde
(3)preparation
117.6 g compounds are added in 2000 mL three-necked bottles
(2), 231.8 g Anhydrous potassium carbonates, 146.2 g methylene bromides, 3 g cupric oxide, 1200 mL dimethyl sulfoxide (DMSO), external oil bath, temperature control 112
oc reacts 4 h.Cooling, carefully pours into reaction solution in 10 L water, stirs 1 h.Suction filtration, washing, dry, obtain pale solid 119.5 g, yield 94.8%.Tetrahydrofuran-ethyl alcohol recrystallization, obtains pale solid 106.5 g, yield: 84%.
Embodiment four:
3-methoxyl group
-4,5-methylene dioxo group benzaldehyde
(3)preparation
117.6 g compounds are added in 2000 mL three-necked bottles
(2), 231.8 g Anhydrous potassium carbonates, 85 g methylene dichloride, 3 g cupric oxide, 1200 mL dimethyl sulfoxide (DMSO), the potassiumiodide of catalytic amount, external oil bath, temperature control 112
oc reacts 4 h.Cooling, carefully pours into reaction solution in 6 L water, stirs 1 h.Suction filtration, washing, dry, obtain pale solid 109.5 g, yield 85.9%.Ethyl alcohol recrystallization, obtains pale solid 101.2 g, yield: 79.4%.
Embodiment five:
3-methoxyl group
-4,5-methylene-dioxy
-
β-
nitrostyrolene
(4)preparation
81g compound is added in 1000 mL three-necked bottles
(3), 55 g Nitromethane 99Min.s, 34.7g amine acetate, 405 mL Glacial acetic acid, back flow reaction 5h.Be cooled to room temperature, suction filtration, anhydrous methanol washs, dry, obtains yellow solid 75g, yield: 75%.
Embodiment six:
3-methoxyl group
-4,5-methylene-dioxy phenethylamine hydrochloride
(5)preparation
22 g Lithium Aluminium Hydrides are scattered in 500 mL tetrahydrofuran (THF)s, are cooled to about 10 DEG C by external ice-water bath, add 20.2 g compounds in 0.5 h in batches
(4), then heating reflux reaction 1 h, cooling.External ice-water bath, careful dropping 19 mL water.Dropwise, continue stirring 1 h, hold over night.Suction filtration, tetrahydrofuran (THF) washs, anhydrous sodium sulfate drying, concentrated, obtains red liquid 13.7 g, yield 75%.Drip ethanol-hydrogen chloride solution and regulate pH=2, suction filtration, obtains white solid 11.2 g, yield: 57%.
Embodiment six:
3-methoxyl group
-4,5-methylene-dioxy phenethylamine hydrochloride
(5)preparation
400 mL 1mol/L borine tetrahydrofuran solutions are cooled to 5 DEG C, are added dropwise to 22.3 g compounds in 1h by external ice-water bath
(4) tetrahydrofuran solution, then room temperature reaction 1 h, is warming up to back flow reaction 5h, cooling.External ice-water bath, carefully drips water, until there is not bubble, keeps temperature of reaction to be less than 10 DEG C.Dropwise, drip 2N hydrochloric acid 75mL, backflow 2h.Cooling, extracted with diethyl ether three times.Water layer adjusts pH for 13 with 20% aqueous sodium hydroxide solution, and extraction into ethyl acetate three times, saturated common salt water washing three times, anhydrous sodium sulfate drying spends the night.Suction filtration, filtrate concentrates, and obtains reddish-brown oily matter.Under ice bath, drip ethyl acetate-hydrogen chloride solution and regulate pH=2, suction filtration, obtains white solid 15.1 g, yield: 75.8%.
Embodiment seven: 3-trichloromethyl-6,7-dimethoxvbenzofuran ketone (
6) synthesis
98.4 g Chloral Hydrates are dissolved in the 250 mL vitriol oils, add 91 g 2,3-dimethoxybenzoic acids, after sealing stirring 10 h, add 2 g sodium iodides, continue reaction 26h.Reaction solution is carefully poured in the mixed solution of 1L frozen water and 1.5L methylene dichloride, vigorous stirring.Separatory, dichloromethane layer is washed to neutrality, and 5% sodium hydroxide solution regulates pH=10, and saturated sodium-chloride washs, anhydrous sodium sulfate drying.Concentrated, obtain white solid 72.3 g, yield 46.2%.
Embodiment eight:
6,7-dimethoxvbenzofuran ketone
-3-carboxylic acid
(7)preparation
46.6 g sodium hydroxide are dissolved in 233 mL water, are heated to 85
oc, adds 46.6 g compounds in batches in 0.5 h
6, reflux 4 h, slightly cold, add 2 g gacs, reflux 0.5 hr, filtered while hot.Cooling, external ice-water bath, drips concentrated hydrochloric acid and regulates pH=1, stir, separate out a large amount of solid, refrigerated overnight.Suction filtration, washing, dry, obtain white solid 33.7 g, yield 94.6%.
Embodiment nine: 6,7-dimethoxvbenzofuran ketone-3-acyl chlorides (
8) synthesis
By 11g compound
(7)be dissolved in 35 mL sulfur oxychlorides, reflux 1.5h, concentrate to obtain acyl chlorides 11.43g, yield 99.2%.Be directly used in next step reaction.
Embodiment ten:
n-
β-(3-
methoxyl group
-4,5-methylenedioxyphenyl) ethyl
-6', 7'-dimethoxvbenzofuran ketone
-3-acid amides
(9)preparation
By 12.7g compound
(5)soluble in water, under ice bath, drip NaOH solution, stir 20 min, dichloromethane extraction, organic layer is washed, and saturated NaCl washes, anhydrous sodium sulfate drying.Filtering siccative, is added to the CH of compound (8) by the dichloromethane extraction drop of compound (5)
2cl
2in solution, add salt of wormwood, rise to room temperature reaction 5 h, suction filtration, filtrate uses the hydrochloric acid of 0.5 mol/L, 5% solution of potassium carbonate, water, saturated common salt water washing respectively, and anhydrous sodium sulfate drying, obtains white solid 8.7 g, and yield is 84%.
Embodiment 11: (±)-1-[9-(3 ', 4 '-dimethoxvbenzofuran ketone group)]-8-methoxyl group-6,7-methylene-dioxy-3,4-dihydro-isoquinoline
(10)preparation
By 20.8g compound
10be dissolved in 140mL phosphorus oxychloride, reflux 1.5h.Cooling, by reaction solution impouring frozen water, suction filtration, filtrate is adjusted neutral with strong aqua.Separate out a large amount of yellow solid, suction filtration, obtain yellow solid 16.5g, yield 84%.Be dissolved in by solid in 165mL ethyl acetate, adjust pH to be 2 with hydrochloric acid, separate out solid, suction filtration, filtrate concentrates, and obtains product 8.66g, yield 43.9%.
Embodiment 12: (±)-E-1-[9-(3 ', 4 '-dimethoxvbenzofuran ketone group)]-8-methoxyl group-6,7-methylene-dioxy-1,2,3,4-tetrahydroisoquinoline
(11)preparation
By 8.66g compound
11be dissolved in 270mL dehydrated alcohol, external ice-water bath cooling, adds 3.03g sodium borohydride in batches, reaction 12h.Careful dropping 2mL water, suction filtration, drips HCl-EtOH and adjusts pH for acid in filtrate.Separate out white solid, suction filtration obtains 7.62g, yield 87.5%.
Embodiment 13:
l-(R, S)-1-[9-(3 ', 4 '-dimethoxvbenzofuran ketone group)]-8-methoxyl group-6,7-methylene-dioxy-1,2,3,4-tetrahydroisoquinoline (
12) synthesis
By 6.0g compound
11be dissolved in the mixing solutions of 200mL acetone, drip the levotartaric acid 4.95g solution with 40ml acetone solution, dropwise rear continuation stirring 6 hours.Suction filtration, filtrate concentrates, and add wet chemical and regulate pH=9, chloroform extraction, saturated sodium-chloride washs, anhydrous sodium sulfate drying, concentrated, obtains off-white color solid 2.13g, yield 40.1%(C=0.5,
=135o, CHCl
3).
Embodiment 14:
l-(R, S)-1-[9-(3 ', 4 '-dimethoxvbenzofuran ketone group)]-8-methoxyl group-6,7-methylene-dioxy-1,2,3,4-tetrahydroisoquinoline (
12) synthesis
By 6.0g compound
11be dissolved in the mixing solutions of 200mL acetone/isopropanol, drip the levorotation benzhydryl formyl tartrate 5.83g solution with 55ml acetone solution, dropwise rear continuation stirring 6 hours.Suction filtration, filtrate concentrates, and add wet chemical and regulate pH=9, chloroform extraction, saturated sodium-chloride washs, anhydrous sodium sulfate drying, concentrated, obtains off-white color solid 2.53g, yield 42.3%(C=0.5,
=135o, CHCl
3).
Embodiment 15:
l-(R, S)-1-[9-(3 ', 4 '-dimethoxvbenzofuran ketone group)]-8-methoxyl group-6,7-methylene-dioxy-1,2,3,4-tetrahydroisoquinoline (
12) synthesis
By 6.0g compound
11be dissolved in the mixing solutions of 300mL acetone/water, drip the levotartaric acid 4.95g solution with 40ml acetone solution, dropwise rear continuation stirring 6 hours.Suction filtration, filtrate concentrates, and add wet chemical and regulate pH=9, chloroform extraction, saturated sodium-chloride washs, anhydrous sodium sulfate drying, concentrated, obtains off-white color solid 1.86g, yield 37.6%(C=0.5,
=135o, CHCl
3).
Embodiment 16:
l-(R, S)-1-[9-(3 ', 4 '-dimethoxvbenzofuran ketone group)]-2-methyl-8-methoxyl group-6,7-methylene-dioxy-1,2,3,4-tetrahydroisoquinoline (
noscapine) synthesis
By 4.0g (10mmol) compound
13be dissolved in 48.8mL formic acid, add 37% formaldehyde 10mL, heating, backflow 30min, cooling, concentrated, add 200mL10% hydrochloric acid.External ice-water bath, with strong aqua neutralization, separates out solid.Suction filtration, obtains pale solid 2.89g, yield 73.0%(C=0.5,
be 186 °, CHCl
3).
Claims (16)
1. the synthetic method of Noscapine, is characterized in that, prepares by the following method:
A. Vanillin is dissolved in protonic acid, drips bromine, obtain 3-methoxyl group-4-hydroxyl-5-bromobenzaldehyde (1) through bromo-reaction; Described protonic acid be in formic acid, acetic acid any one;
B. 3-methoxyl group-4-hydroxyl-5-bromobenzaldehyde (1) is hydrolyzed in the basic conditions and obtains 3-methoxyl group-4,5-Dihydroxy benzaldehyde (2);
C. 3-methoxyl group-4,5-Dihydroxy benzaldehyde (2) is in non-protonic solvent, adds mineral alkali, is obtained by reacting 3-methoxyl group-4,5-methylene dioxo group benzaldehyde (3) with cyclizing agent generation cyclization;
D. 3-methoxyl group-4,5-methylene dioxo group benzaldehyde (3) and Nitromethane 99Min. condensation obtain 3-methoxyl group-4,5-methylene-dioxies-beta-nitrostyrene (4);
E. 3-methoxyl group-4,5-methylene-dioxies-beta-nitrostyrene (4) obtains 3-methoxyl group-4,5-methylene-dioxy phenethylamine hydrochloride (5) through reduction, salify;
F. 2,3-dimethoxybenzoic acids obtain 3-trichloromethyl-6,7-dimethoxvbenzofuran ketone (6) with Chloral Hydrate cyclization under acid solvent condition;
G. 3-trichloromethyl-6,7-dimethoxvbenzofuran ketone (6) is hydrolyzed in the basic conditions and obtains 6,7-dimethoxvbenzofuran ketone-3-carboxylic acid (7);
H. 6,7-dimethoxvbenzofuran ketone-3-carboxylic acid (7) obtain 6,7-dimethoxvbenzofuran ketone-3-acyl chlorides (8) through halogenating reaction;
I. 3-methoxyl group-4,5-methylene-dioxy phenethylamine hydrochloride (5) and 6,7-dimethoxvbenzofuran ketone-3-acyl chlorides (8) docking obtains N-β-(3-methoxyl group-4,5-methylenedioxyphenyl) ethyl-6', 7'-dimethoxvbenzofuran ketone-3-acid amides (9);
J. N-β-(3-methoxyl group-4,5-methylenedioxyphenyl) ethyl-6', 7'-dimethoxvbenzofuran ketone-3-acid amides (9) obtains (±)-1-[9-(3 ' under the effect of cyclization reagent, 4 '-dimethoxvbenzofuran ketone group)]-8-methoxyl group-6,7-methylene-dioxy-3,4-dihydro-isoquinoline (10);
K. (±)-1-[9-(3 ', 4 '-dimethoxvbenzofuran ketone group)]-8-methoxyl group-6,7-methylene-dioxy-3,4-dihydro-isoquinoline (10) obtains (±)-E-1-[9-(3 ' through reduction reaction, 4 '-dimethoxvbenzofuran ketone group)]-8-methoxyl group-6,7-methylene-dioxy-1,2,3,4-tetrahydroisoquinoline (11);
L. (±)-E-1-[9-(3 ', 4 '-dimethoxvbenzofuran ketone group)]-8-methoxyl group-6,7-methylene-dioxy-1,2,3,4-tetrahydroisoquinoline (11) splits through chiral reagent and obtains l-(R, S)-1-[9-(3 ', 4 '-dimethoxvbenzofuran ketone group)]-8-methoxyl group-6,7-methylene-dioxy-1,2,3,4-tetrahydroisoquinoline (12);
M. l-(R, S)-1-[9-(3 ', 4 '-dimethoxvbenzofuran ketone group)]-8-methoxyl group-6,7-methylene-dioxy-1,2,3,4-tetrahydroisoquinoline (12) obtains target product Noscapine through methylation reaction.
2. synthetic method according to claim 1, is characterized in that, the protonic acid described in step a is acetic acid, and temperature of reaction is room temperature.
3. synthetic method according to claim 1, is characterized in that, the solvent in step b is any one or its mixed solvent in ethanol, Virahol, water; Alkali is selected from sodium carbonate, sodium hydroxide, potassium hydroxide, and temperature of reaction is reflux temperature.
4. synthetic method according to claim 1, is characterized in that, the solvent in step b is water, and alkali is sodium hydroxide.
5. synthetic method according to claim 1, is characterized in that, the solvent described in step c be in DMF, dimethyl sulfoxide (DMSO) any one, cyclization reagent is methylene dichloride or methylene bromide, and temperature of reaction is reflux temperature.
6. synthetic method according to claim 1, is characterized in that, the solvent in step e be in anhydrous diethyl ether, tetrahydrofuran (THF) any one, reductive agent is lithium aluminium hydride or borine tetrahydrofuran (THF), or Shi Yong Palladium carbon catalytic hydrogenation reduction.
7. synthetic method according to claim 1, is characterized in that, the solvent in step e is tetrahydrofuran (THF).
8. synthetic method according to claim 1, is characterized in that, the acid solvent described in step f be in the vitriol oil, acetic acid any one, temperature of reaction is 20 DEG C-80 DEG C.
9. synthetic method according to claim 1, is characterized in that, the acid solvent described in step f is the vitriol oil.
10. synthetic method according to claim 1, is characterized in that, the solvent in step g is any one or mixed solvent in ethanol, Virahol, water; Alkali is selected from sodium carbonate, sodium hydroxide or potassium hydroxide, and temperature of reaction is reflux temperature.
11. synthetic methods according to claim 1, is characterized in that, the solvent in step g is water, and alkali is sodium hydroxide.
12. synthetic methods according to claim 1, is characterized in that, the solvent in step j be in toluene, glycol dimethyl ether any one, cyclization reagent is selected from phosphorus oxychloride, polyphosphoric acid, and temperature of reaction is reflux temperature.
13. synthetic methods according to claim 1, is characterized in that, the solvent in step l is any one or mix reagent in acetone, Virahol, water, and resolution reagent is tartrate, dibenzoyl tartaric acid or camphorsulfonic acid.
14. synthetic methods according to claim 1, is characterized in that, the solvent in step l is acetone-isopropanol mixed solvent, and resolution reagent is dibenzoyl tartaric acid.
15. synthetic methods according to claim 1, is characterized in that, the methylating reagent described in step m is formaldehyde/formic acid, formaldehyde/sodium borohydride or methyl iodide, and temperature of reaction is reflux temperature.
16. synthetic methods according to claim 1, is characterized in that, the methylating reagent described in step m is formaldehyde/formic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110049910.5A CN102653542B (en) | 2011-03-02 | 2011-03-02 | Synthetic method of narcotine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110049910.5A CN102653542B (en) | 2011-03-02 | 2011-03-02 | Synthetic method of narcotine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102653542A CN102653542A (en) | 2012-09-05 |
| CN102653542B true CN102653542B (en) | 2014-12-17 |
Family
ID=46729287
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201110049910.5A Expired - Fee Related CN102653542B (en) | 2011-03-02 | 2011-03-02 | Synthetic method of narcotine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102653542B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103214493B (en) * | 2013-05-10 | 2015-12-23 | 南京友杰医药科技有限公司 | The selective reduction of chirality B catalyst is utilized to prepare (-) α-Noscapine |
| CN112110932B (en) * | 2019-06-21 | 2021-12-28 | 沈阳药科大学 | Method for synthesizing phthalide tetrahydroisoquinoline compound by tandem cyclization strategy |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0219371A2 (en) * | 1985-09-06 | 1987-04-22 | Mitsubishi Kasei Corporation | Anisole derivatives |
| EP0617022A1 (en) * | 1993-02-25 | 1994-09-28 | Banyu Pharmaceutical Co., Ltd. | 6,7, dialkoxy-3,4-dihydroisoquinolin-8-ol, process for preparation thereof and process for preparation of 6,7-dialkoxy-1,2,3,4-tetrahydroisoquinolin-8-ol using the compound |
| CN101775021A (en) * | 2010-01-08 | 2010-07-14 | 沈阳药科大学 | Method for selective synthesis of alpha-narcotine with participation of blockage group |
-
2011
- 2011-03-02 CN CN201110049910.5A patent/CN102653542B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0219371A2 (en) * | 1985-09-06 | 1987-04-22 | Mitsubishi Kasei Corporation | Anisole derivatives |
| EP0617022A1 (en) * | 1993-02-25 | 1994-09-28 | Banyu Pharmaceutical Co., Ltd. | 6,7, dialkoxy-3,4-dihydroisoquinolin-8-ol, process for preparation thereof and process for preparation of 6,7-dialkoxy-1,2,3,4-tetrahydroisoquinolin-8-ol using the compound |
| CN101775021A (en) * | 2010-01-08 | 2010-07-14 | 沈阳药科大学 | Method for selective synthesis of alpha-narcotine with participation of blockage group |
Non-Patent Citations (2)
| Title |
|---|
| CVI.-Synthesis of Cotarnine;Arthur Henry Salway;《Journal of the Chemical Society》;19100101;第1208-1219页 * |
| SYNTHESIS OF CERTAIN COMPOUNDS RELATED TO α-FAGARINE;C.ERNST REDEMANN,等;《Journal of Organic Chemistry》;19481130;第13卷(第6期);第886–890页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102653542A (en) | 2012-09-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2818171B1 (en) | Antitumor aza-benzo[f]azulen derivative, method for preparing same, and use thereof | |
| CA2241551A1 (en) | Coralyne analogs as topoisomerase inhibitors | |
| CN105985306B (en) | The fully synthetic preparation method of natural products flavone compound | |
| CN102796096B (en) | Hexahydro dibenzo [a, g] quinolizine compounds, its preparation method, pharmaceutical composition and application thereof | |
| CN102653542B (en) | Synthetic method of narcotine | |
| CN101775021B (en) | Method for selective synthesis of alpha-narcotine with participation of blockage group | |
| CN102030716A (en) | Method for preparing gefitinib | |
| CN105294583A (en) | Synthesizing method of 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid | |
| Mackay et al. | Synthesis of quaternary benzo [c] phenanthridine alkaloids and their analogues | |
| CN112645887B (en) | Preparation method of quinazolinone derivative | |
| US20150164870A1 (en) | Use and preparation method of berberine compounds | |
| CN112110932B (en) | Method for synthesizing phthalide tetrahydroisoquinoline compound by tandem cyclization strategy | |
| CN104072426B (en) | A kind of preparation method of cancer therapy drug | |
| CN102321058A (en) | Method for synthesizing dronedarone hydrochloride | |
| Zimmerman et al. | Synthesis and analgesic properties of N-substituted trans-4a-aryldecahydroisoquinolines | |
| AU2002224086B1 (en) | Indole derivatives and use thereof in medicines | |
| CN101033228B (en) | Method of preparing 14-hydroxy-7,8-dihydromorphone | |
| CN102120742B (en) | Preparation method of tetrabenazine | |
| CN105348279B (en) | A kind of (2 thienyl) base esters of 2 hydroxyacetic acid quinine 3 of R 2,2 2 and its preparation and application | |
| CN109467506A (en) | A kind of preparation method of substituted phenylacetic acid derivative | |
| CN110684003A (en) | Simple and efficient total synthesis method of icaritin and derivatives thereof | |
| KR20070007041A (en) | Tricyclic imidazopyridines for use as gastric secretion inhibitors | |
| CN103965104B (en) | A kind of preparation method of tyrosine kinase inhibitor and its intermediate | |
| CN103044327B (en) | Preparation method of dextromethorphan | |
| CN107778238A (en) | A kind of new synthetic method of the ketone of 3,4 dihydro-isoquinoline 1 and isoindoline 1 ketone derivatives |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20141217 |