CN103408439A - Chemical synthetic method of norbelladine - Google Patents
Chemical synthetic method of norbelladine Download PDFInfo
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- CN103408439A CN103408439A CN2013102685117A CN201310268511A CN103408439A CN 103408439 A CN103408439 A CN 103408439A CN 2013102685117 A CN2013102685117 A CN 2013102685117A CN 201310268511 A CN201310268511 A CN 201310268511A CN 103408439 A CN103408439 A CN 103408439A
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Abstract
The present invention relates to one kind to drop the chemical synthesis process of belladonna lily pyridine as shown in formula (I).
This method, for raw material, in organic solvent, reacts in 20 DEG C~50 DEG C 1 by using catalyst appropriate and reducing agent~for 24 hours, reaction product filtering isolates and purifies filter cake to obtain drop belladonna lily pyridine with 3,4- 4-dihydroxy benzaldehyde and 4- hydroxyphenethylamine. The advantages that this method has easy to operate, and equipment investment is few, and production cost is low, and reaction yield is high, is suitable for industrial production. The beneficial effects of the present invention are: belladonna lily pyridine can be dropped with the important secondary metabolite of simple step and reactant synthesis lycoris plants, curative effect medicine galanthamine is synthesized for genetic engineering and provides a new approach.
Description
Technical field
The present invention relates to the production of a kind of employing chemical synthesis process and fall the method for belladonna lily pyridine (norbelladine), be specifically related to a kind of 3,4-Dihydroxy benzaldehyde and 4-hydroxyphenethylamine are raw material, by adopting suitable reductive agent, it are reduced to the method for falling the belladonna lily pyridine.
Background technology
Falling the belladonna lily pyridine is the Tyrosine analog derivative, is also a kind of alkaloid.Can be from many Amaryllidaceaes (Amaryllidaceae) plant, extracting and obtain, be the important precursor of the short-tube lycoris Alkaloid such as biosynthesizing lycoremine in plant materials.Lycoremine is the active drug for the treatment of clinically at present mild to moderate alzheimer's disease (senile dementia), poliomyelitis and other nervous system disorders.At present, due to problems such as the complete synthesis cost of chemistry and productive rates, lycoremine still be take plant extract as main.In addition, in existing synthetic method, there are no the chemosynthesis report that falls the belladonna lily pyridine.
Therefore, adopt the method production of chemosynthesis to fall the belladonna lily pyridine, using this crucial substrate as the biosynthesizing lycoremine, and be applied to the detection of the biological enzyme (being mainly the oxygen methyltransgerase) of its degraded of catalysis, in future, producing in the process of lycoremine by gene engineering method is indispensable.And the intersection of chemistry and two kinds of subjects of bio-pharmaceuticals is had great importance.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of synthetic method of falling the belladonna lily pyridine, and the method is easy and simple to handle, quality product is excellent, foreign matter content is few, production cost is low, reaction yield is high.The activity that can be used for plant materials oxygen methyltransgerase detects.
4-[[2-of the present invention (4-hydroxyphenyl) ethylamino]] benzene-1,2-glycol (falling the belladonna lily pyridine) is suc as formula the compound shown in (I).
The chemical synthesis process that falls the belladonna lily pyridine of the present invention is as follows:
(a) utilize 3 shown in formula (II), 4-hydroxyphenethylamine (tyrasamine) shown in 4-Dihydroxy benzaldehyde and formula (III) is raw material, it is dissolved in to (as methyl alcohol, ethanol or other soluble organic solvent) in organic solvent, the catalyzer (Lewis acid) that adds aequum, control corresponding temperature of reaction (20 ℃～100 ℃) and reaction times, constantly stirring down to a large amount of orange-yellow Precipitations, cooling rear decompress filter obtains the crude product product.
(b) crude product product above-mentioned steps obtained carries out a small amount of ethanol solution washing, after low-temperature vacuum drying, obtains intermediate product compound (IV) standby.Concrete response path is shown in following formula:
(c) the orange-yellow precipitation of gained in above-mentioned steps is dissolved in organic solvent (anhydrous methanol or dehydrated alcohol), add a certain amount of reductive agent or catalyzer (as hydroborate, Lithium Aluminium Hydride etc.), under 0 ℃～10 ℃ low temperature, continuous stirring reaction, fully after reaction, that the gained reaction solution is standing, the filtrate extraction, underpressure distillation to crystal is separated out.
(d) with a small amount of solvent wash crystal, as inadequate as the gained crystal purity, available appropriate solvent recrystallization is processed, and finally obtains formula (I).Reaction formula is as follows:
● the selected raw material of the present invention is 0412 and 4-hydroxyphenethylamine (tyrasamine), and directly mixed dissolution is in reaction solvent for this raw material, and preferred organic solvent is anhydrous methanol or dehydrated alcohol etc.
● the selected raw material of the present invention can mix and add the reaction solvent reaction, also can successively add the reaction solvent reaction, and preferably application of sample, sequentially for first adding formula (II), then adds formula (III) under nitrogen protection; Wherein the mol ratio of preferred formula (II) compound and formula (III) compound is 1: 1～3: 2; The volume mass ratio of solvent and formula (II) compound is 8～20mL/g.
● the selected catalyzer of the present invention is Lewis acid, and preferred catalyzer is Glacial acetic acid.
● temperature of reaction of the present invention is 20 ℃～60 ℃, is more preferably 40～50 ℃; Reaction times is 0～24h, and the preferred described reaction times is 6～12h.
● the selected reductive agent of the present invention is hydroborate or hydrogen, and preferred reductive agent is hydroborate, is sodium borohydride or POTASSIUM BOROHYDRIDE etc. more specifically; And hydroborate is dissolved in 1% sodium hydroxide and uses; Compound (IV) is 1: 2～4 with the consumption mol ratio of reductive agent.
● low-temp reaction condition of the present invention is 0～10 ℃, and preferred low-temp reaction temperature is 4 ℃.
● if during the underpressure distillation of the present invention's reaction solution, obtain thick liquid, need to separate through column chromatography, get final product to obtain target product, target product detects (HPLC-MS) through high performance liquid chromatography and GC-MS, final hard objectives product formula (I) compound.
● the invention has the beneficial effects as follows: can fall the belladonna lily pyridine with the important secondary metabolite of simple step and the synthetic short-tube lycoris of reactant, combined coefficient is high, for the synthetic lycoremine of genetically engineered provides the substrate basis, is applicable to industry's enlarging production.
The accompanying drawing explanation
Fig. 1 is that HPLC that the belladonna lily pyridine falls in formula (I) target product detects collection of illustrative plates (chromatographic condition is: moving phase is acetonitrile and water; The detection wavelength is 280nm; Flow velocity is 1mL/min; Applied sample amount is 10 μ l);
Fig. 2 is that formula (I) target product falls the mass spectrometric detection collection of illustrative plates of belladonna lily pyridine (the mass spectrum condition is: the ESI under positive ion mode
+Mass spectrum).
Embodiment
Below adopt the mode of specific embodiment to explain particularly the present invention, but the present invention is not limited to embodiment.
Embodiment 1
By formula (II) compound 3,4-Dihydroxy benzaldehyde 0.4g is dissolved in the 15mL dehydrated alcohol, in 40 ℃ of reflux continuous situation about stirring, add formula (III) compound 4-hydroxy base phenylethylamine (tyrasamine) 0.4g, add rear continuation and stir 10min, drip 1mL Glacial acetic acid catalyzed reaction 12h.After reaction finishes, adopt immediately the Büchner funnel decompress filter, filter cake with after a small amount of absolute ethanol washing in 50 ℃ of lower vacuum-dryings, obtain orange/yellow solid intermediate product (IV), the calculating reaction yield is 75.96%.
After reaction finishes, reaction product is placed in to room temperature and places 8h, use afterwards the Büchner funnel decompress filter, other condition preparation process, all with embodiment 1, obtains orange/yellow solid intermediate product (IV), yield 99.73%.
Temperature of reaction changes 50 ℃ into, and other condition preparation process is all with embodiment 1, and result obtains obtaining orange/yellow solid intermediate product (IV), yield 68.78%
Embodiment 4
The orange-yellow precipitation of formula (IV) the intermediate product 0.2g that embodiment 2 is obtained is dissolved in the 2mL dehydrated alcohol, under 4 ℃ of conditions, constantly stir and dropwise drip the sodium hydroxide solution (the 1.5g sodium borohydride is dissolved in 4mL1% sodium hydroxide) of sodium borohydride, after stirring reaction 8h, add saturated ammonium chloride solution quencher reaction, 4 ℃ of stand at low temperature, to separating out pale precipitation, suction filtration, filtrate is with after ethyl acetate extraction, merging, last underpressure distillation solid is separated out, combining solid.After recrystallization, obtain formula (I) purpose product.
Embodiment 5
The orange-yellow precipitation of formula (IV) the intermediate product 0.22g that embodiment 2 is obtained is dissolved in the 8mL Glacial acetic acid, take palladium carbon 1g in reaction flask, drip the 2mL Glacial acetic acid and rush wall, vacuumize, pass into the continuous stirring reaction 12h of hydrogen, obtain brown solution after reaction finishes, suction filtration is removed palladium carbon, underpressure distillation obtains thick liquid, purifies by chromatographic column, obtains formula (I) target product.
The target product that falls belladonna lily pyridine chemosynthesis of above example detects sees accompanying drawing.
Claims (9)
- One kind suc as formula shown in (I) fall the belladonna lily pyridine (4-[[2-(4-hydroxyphenyl) ethylamino]] benzene-1, the 2-glycol) synthetic method, described chemical synthesis process is as follows: formula (II) compound and formula (III) compound are joined in organic solvent, reflux stirs and spends the night to a large amount of orange-yellow Precipitations under Lewis acid effect, decompress filter must precipitate, absolute ethanol washing, 50 ℃ of vacuum-dryings obtain formula (IV) compound; Formula (IV) compound is dissolved in organic solvent, low-temp reaction certain hour under the reducing catalyst effect, the gained reaction solution is standing, the filtrate extraction, underpressure distillation is to dry, and solid is separated out, and the belladonna lily pyridine must fall in recrystallization.
- 2. the preparation method who falls the belladonna lily pyridine according to claim 1, it is characterized in that: the raw material of selecting is 3, directly mixed dissolution is in reaction solvent for 4-Dihydroxy benzaldehyde and 4-hydroxyphenethylamine (tyrasamine), this raw material, and preferred organic solvent is anhydrous methanol or dehydrated alcohol etc.
- 3. the preparation method who falls the belladonna lily pyridine according to claim 1, it is characterized in that: selected raw material can mix and add the reaction solvent reaction, also can successively add the reaction solvent reaction, preferably application of sample, sequentially for first adding formula (II), then adds formula (III) under nitrogen protection; Wherein the mol ratio of preferred formula (II) compound and formula (III) compound is 1: 1～3: 2; The volume mass ratio of solvent and formula (II) compound is 8～20mL/g.
- 4. the preparation method who falls the belladonna lily pyridine according to claim 1, it is characterized in that: selected catalyzer is Lewis acid, preferred catalyzer is Glacial acetic acid.
- 5. the preparation method who falls the belladonna lily pyridine according to claim 1, it is characterized in that: temperature of reaction is 20 ℃～60 ℃, is more preferably 40～50 ℃; Reaction times is 0～24h, and the preferred described reaction times is 6～12h.
- 6. the preparation method who falls the belladonna lily pyridine according to claim 1, it is characterized in that: the reductive agent of selecting is hydroborate or hydrogen/10% palladium carbon, preferred reductive agent is hydroborate, is sodium borohydride or POTASSIUM BOROHYDRIDE etc. more specifically; And hydroborate is dissolved in 1% sodium hydroxide and uses; Compound (IV) is 1: 2～4 with the consumption mol ratio of reductive agent.
- 7. the preparation method who falls the belladonna lily pyridine according to claim 1, it is characterized in that: the low-temp reaction condition is 0～10 ℃, preferred low-temp reaction temperature is 4 ℃.
- 8. the preparation method who falls the belladonna lily pyridine according to claim 1, it is characterized in that: if obtain thick liquid during the reaction solution underpressure distillation, need to separate through column chromatography, get final product to obtain target product, target product detects (HPLC-MS) through high performance liquid chromatography and GC-MS, final hard objectives product formula (I) compound.
- 9. the preparation method who falls the belladonna lily pyridine according to claim 1, it is characterized in that: can fall the belladonna lily pyridine with the important secondary metabolite of simple step and the synthetic lycoris plants of reactant, combined coefficient is high, for the synthetic lycoremine of genetically engineered provides the substrate basis, be applicable to industry's enlarging production.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112753410A (en) * | 2021-01-13 | 2021-05-07 | 上海科立特农科（集团）有限公司 | Method for improving alkaloid content in lycoris by using exogenous substances |
| CN113376281A (en) * | 2021-06-10 | 2021-09-10 | 上海市农业科学院 | Method for simultaneously detecting 14 metabolites in lycoris plant alkaloid synthesis pathway |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1687064A (en) * | 2005-04-18 | 2005-10-26 | 昆明圣火制药有限责任公司 | Synthetic method for preparing fibrauretine of antibiosis anti-inflammatory drug |
| CN101525293A (en) * | 2009-04-17 | 2009-09-09 | 常州市越兴化工有限公司 | Production method of optically active N-benzyl-1-phenylethylamine |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1687064A (en) * | 2005-04-18 | 2005-10-26 | 昆明圣火制药有限责任公司 | Synthetic method for preparing fibrauretine of antibiosis anti-inflammatory drug |
| CN101525293A (en) * | 2009-04-17 | 2009-09-09 | 常州市越兴化工有限公司 | Production method of optically active N-benzyl-1-phenylethylamine |
Non-Patent Citations (3)
| Title |
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| SUN-YONG HAN等: "A new lead compound for abscisic acid biosynthesis inhibitors targeting 9-cis-epoxycarotenoid dioxygenase", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| 程广斌等: "间羟基苯乙胺的合成", 《精细石油化工》 * |
| 赵冰等: "N-吡啶香豆素类亚胺化合物的合成与表征", 《化学试剂》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112753410A (en) * | 2021-01-13 | 2021-05-07 | 上海科立特农科（集团）有限公司 | Method for improving alkaloid content in lycoris by using exogenous substances |
| CN113376281A (en) * | 2021-06-10 | 2021-09-10 | 上海市农业科学院 | Method for simultaneously detecting 14 metabolites in lycoris plant alkaloid synthesis pathway |
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Application publication date: 20131127 |