CN106986912A - A kind of synthetic method of betulonic acid amino acid derivativges - Google Patents
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Abstract
The invention discloses a kind of synthetic method of betulonic acid amino acid derivativges, belong to organic chemistry pharmaceutical synthesis field.This method synthesizes betulonic acid with betulinol cheap and easy to get, the betulonic acid for solving to prepare needed for wooden ketone acid amino acid derivativges there is lack of raw materials problem；By betulonic acid and modified lysine, dehydration condensation is carried out, hydrolysis prepares betulonic acid amino acid derivativges, shortens reactions steps, substantially increases the yield of product, and avoid catalytic hydrogenation reaction.Meanwhile, the high income of one of raw material of synthetically prepared betulonic acid amino acid derivativges betulonic acid, up to 83 more than %, purity is high, up to 99.5 more than %.It is synthetically prepared go out betulonic acid amino acid derivativges good water solubility, anti-prostate tumor activity is strong, has good application value to the medicine for developing new anti-prostate tumor.
Description
Technical field
The invention belongs to organic chemistry pharmaceutical synthesis field, and in particular to a kind of synthesis of betulonic acid-amino acid derivativges
Method.
Background technology
Currently, tumour especially malignant tumour is still to endanger one of common disease of human health and life, and only in China
Just there is 1 to die from malignant tumour in per 4-5 died.He result of investigation is shown, in cause of the death ranking, mortality of malignant tumors
Account for first of city dweller's cause of death, the 3rd is occupied in urban residents.Although recent years, antineoplastic has quickly
Development and breakthrough, newtype drug also continuously emerges.But for the treatment of tumor of prostate, so far, it has not been found that
Effective specific drug.
Four major classes can be divided into the source of antineoplastic：Microbe-derived medicine (antitumor antibiotics), chemical synthesis
Medicine, biotechnology medicine, plant origin medicine.Wherein come from plant applied in clinical antineoplastic about 1/3, include plant
The original shape composition and its derivative of thing in itself, wherein including the plant structures such as taxanes, lignanoids, alkaloids and terpene
Type, and terpene point sequiterpene, diterpene, triterpene and triterpene glycoside.Betulinol is the pentacyclic triterpene alkenes for having C-30 skeletons
Compound, integrally maintains the structure of lupane, is very abundant native compound, is present in birch, granatum and leaf, wild jujube
In the plants such as benevolence, the calyx and receptacle of a persimmon, jujube, especially in birch-bark, its content has reached 25% or so of bark dry weight.
Show according to the study：Betulinol and its derivative betulinic acid especially betulonic acid be respectively provided with clearing heat and detoxicating, Adjust-blood lipid,
Improve immunity, anti-inflammatory, improve hair gloss, promote natural on-off cycles of hair growth, anti-inflammatory, anti-dysentery, antipathogen, prostaglandin E2 and
The effects such as nitric oxide production suppression body.Importantly, they show than ever in terms of AntiHIV1 RT activity and antitumor isoreactivity
Target-oriented drug is stronger, mechanism of action is less with, the characteristic that immunosuppressive action is lower, toxic side effect is smaller.Therefore, for
The close attention of the research of betulinol and its this kind of newtype drug of derivative has progressively received drug research person.But birch
The development and application and clinical research of ketone acid, which are received, significantly to be limited, and reason is that its water solubility is very poor, it is extremely difficult to soluble in water,
So that its active anticancer in organism inner cell can only obtain limited very least a portion of performance.For this reason, it may be necessary to high water-soluble
Property lysine to betulonic acid carry out sequence of chemical structural modification, prepare betulonic acid-amino acid derivativges, make it have
Good bioavilability, especially high bioactivity, antitumor activity and good water solubility, are developed into treatment prostatitis
The specific drug of adenoncus knurl, promotes the well-being of mankind.
Michel Evers etal., J. Med. Chem. 39:1056-1068 (1996), N. I. Pe-trenko etal.
, Chemistry of Natural Compounds. 38 (4)：331-339 (2002), tinkling of pieces of jade Zhejiang University of State of Zhao .108-
114 (2007), Zhang little Li etc., Beijing Forestry University journal 33 (1):The documents such as 134-138 (2011), which are reported, uses birch
Wooden ketone acid makees raw material and related amino acid reaction has synthesized betulonic acid-amino acid derivativges, and some documents are also suppressing to it
The activity aspect of growth of tumour cell is studied.Kobayashi etal., J.Org.Chem 66: 6626-6633
(2001)；Zhao et al., J. Org.Chem. 69: 270-279 (2004)；B. B. Saxena etal.
Bioorg. Med. Chem. 14: 6349-6358(2006)；Saxena etal.
Betulonic acid and bad ammonia are reported in US2009/0176753A1 and the grade documents of Chinese patent CN 201280031564. 0
Acid reaction synthesizes the research of betulonic acid-amino acid derivativges related fields, and certain grind also has been carried out to its antitumor activity
Study carefully.But the reaction about betulonic acid and lysine is synthesized by the sequence of chemical reaction of three six small steps of big step above,
Reactions steps are long, and yield is low, and have catalytic hydrogenation reaction.For ease of industrialized developing and application, it is badly in need of preparing work to it at present
Skill is improved.
The content of the invention
Present invention aims at providing, a kind of reactions steps are short, high income betulonic acid-amino acid derivativges synthesis side
Method, is easy to industrial application.
To realize the object of the invention, the present invention carries out dehydration condensation using betulonic acid and modified lysine as raw material,
Further hydrolysis prepares betulonic acid-amino acid derivativges.Synthesized especially by following method：
（1）It is that betulinol is dissolved in organic solvent by compound 1, adds Jones（Jones）Reagent is aoxidized.Reaction knot
Beam, adds quencher quenches.Then, reaction solution is depressurized and rotated, suction filtration extracts filtrate, washed, dry again through column chromatography point
From obtaining compound 2；The organic solvent selects acetonitrile, acetone, tetrahydrofuran etc..
（2）It is that lysine derivative Boc-Lys (Fmoc)-OMe is dissolved in containing weight/mass percentage composition 15% by compound 3
In the organic solvent of alkaline reagent;Question response completely, is poured into mixture of ice and water, adds non-polar solven or low pole solution enters
Row point liquid, removes oil phase.Then aqueous phase is extracted, decompression rotation, the compound 4 of dry good water solubility is Boc-lys-
OMe；The organic solvent selects methanol, ethanol, acetonitrile, acetone, tetrahydrofuran, N,N-dimethylformamide etc..The alkalescence examination
Ammoniacal liquor or methylamine, dimethylamine, trimethylamine, ethamine, diethylamine, triethylamine solution are selected in agent.
（3）Compound 2 is dissolved in organic solvent, alkaline reagent, condensing agent and dehydrating agent is then added and mixes,
Add compound 4 to react, obtain compound 5 i.e. betulonic acid-amino acid derivativges intermediate B A-boc-lys-OMe.Reaction knot
Beam, is post-processed and column chromatographic isolation and purification to sample.
The organic solvent select methanol, ethanol, acetonitrile, acetone, tetrahydrofuran, N,N-dimethylformamide, dichloromethane,
Chloroform or dimethyl sulfoxide (DMSO).
The alkaline reagent selects methylamine, dimethylamine, trimethylamine, ethamine, diethylamine, triethylamine solution etc..
The condensing agent selects I-hydroxybenzotriazole（HOBT）, N- hydroxyl -7- azepine BTAs（HOAT）, benzo three
Nitrogen azoles -1- bases epoxide three（Dimethylamino）Phosphorus hexafluorophosphate（BOP）Deng.
The dehydrating agent choosing is mainly the related substances of Carbodiimides, such as N, N'- Dicyclohexylcarbodiimides
（DCC）, N, N'- DICs（DIC）, 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride（EDC
HCl）Deng；According to the extent of reaction situation of dehydration condensation, can be properly added can be catalyzed the effective catalyst 4- bis- of the reaction
Methylamino pyridine（DMAP）.
（4）Compound 5 is dissolved in organic solvent miscible with water, first adds water, added basic hydrolysis reagent and enter
Row reaction.Reaction terminates, and product is post-processed and column chromatographic isolation and purification obtains target product betulonic acid-amino acid and spread out
Biological BA-boc-lys-OH.
The organic solvent selects methanol, ethanol, acetone, tetrahydrofuran.
The basic hydrolysis reagent select water lithium hydroxide, potassium hydroxide, sodium hydroxide, lithium carbonate, potassium carbonate, sodium carbonate,
Sodium acid carbonate, saleratus etc..
Step（1）Middle use L9 (34) orthogonal, optimal processing parameter is betulinol：The ratio of organic solvent is
1：50（g ：mL）, the ratio of betulinol and Jones reagents is 1：12（g ：mL）, reaction temperature is -10 DEG C, and the reaction time is 4
h。
Step（3）2 h are reacted under the conditions of preferred cryostat-10-5 DEG C when middle compound 4 is added, then in room temperature（25-30
℃）48 h of lower reaction.
Innovative point of the present invention and advantage are：This method is with betulinol cheap and easy to get（Betulinol contains in Japanese birch bark
Amount up to 25%）Synthetically prepared betulonic acid, there is lack of raw materials for the betulonic acid needed for the wooden ketone acid-amino acid derivativges of solution preparation
Problem, meanwhile, the high income of the betulonic acid of synthesis, up to 83 more than %, purity is high, up to 99.5 more than %.By betulonic acid
Dehydration condensation is carried out with modified lysine, hydrolysis prepares betulonic acid-amino acid derivativges, shorten reaction step
Suddenly, the yield of product is substantially increased（Total recovery >=64.0%）, and avoid catalytic hydrogenation reaction.It is synthetically prepared go out birch
Ketone acid-amino acid derivativges good water solubility, anti-prostate tumor activity is strong, has to the medicine for developing new anti-prostate tumor
Good application value.
Brief description of the drawings
The HPLC collection of illustrative plates for the betulonic acid product that Fig. 1 is prepared for the present invention；
Fig. 2 is the HPLC collection of illustrative plates of betulonic acid standard items；
The mass spectrogram for the betulonic acid product that Fig. 3 is prepared for the present invention.
Embodiment
For the present invention is better described, embodiment is as follows：
Embodiment 1
（1）The betulinol for weighing 12.00 g is added in 600 mL acetone solvent, 40 DEG C or so the lower min of heating stirring 30,
It is then cooled to -10 DEG C.Then 144.0 g of brand-new Jones reagents are added dropwise in above-mentioned reaction bulb.Instead
Temperature is answered to be maintained at -10 DEG C, maintenance reaction time 4h.After reaction terminates, 600 mL ethanol examination is added dropwise under the conditions of -10 DEG C
Agent is quenched.Then proceed to stir 60 min.600 mL water are finally added dropwise and are stirred for 30 min.Decompression rotation is carried out to above-mentioned reaction solution
Turn, filter out blackish green precipitation.Raffinate is extracted at least 3 times with tetrahydrofuran, is then washed 3 times with saturated common salt, finally with anhydrous
Na2SO4It is dried overnight.Filtering, rotates to obtain light green solid i.e. betulonic acid crude product.By a small amount of dichloromethane of betulonic acid crude product
After alkane dissolving, upper chromatography post separation, eluant, eluent dichloromethane：Ethyl acetate=2：1、1：1、1：2 graded series mixed solvents,
Target fraction containing betulonic acid is merged into drawing to do, is subsequently placed in vacuum drying chamber at 45 DEG C and dries 24 h, is prepared
The g of betulonic acid product 10.80 that purity is 99.5 % is obtained, yield is 87.6 %.
（2）Weigh lysine derivative Boc-Lys (Fmoc)-OMe（Compound 3）13.75 g are dissolved in containing quality
The N of the triethylamine of percentage 15%, N- dimethylformamides（DMF）In solvent, room temperature（25-30 DEG C）0.5 h of lower reaction.Question response
Completely, it is poured into 200 mL mixture of ice and water, stirs.Then by this mixture 20 mL ethyl acetate and 100 mL stones
The mixed solvent of oily ether washed once, and point liquid discards upper oil phase.Aqueous phase is added after appropriate NaCl, is extracted with ethyl acetate at least
15 times.Last combined ethyl acetate organic phase, uses anhydrous Na2SO4 is dried overnight.Filtering, decompression rotation, obtains solution shape material i.e.
The Boc-lys-OMe of the DMF containing part is modified lazy propylhomoserin（Compound 4）；
（3）By step（1）The 10.20 g betulonic acids prepared are dissolved in 70 mL anhydrous propanones, then add 13.10 g
BOP, 4.94 g EDC HCl and 4.67 mL trimethylamine, stir 30 min under the conditions of -10--5 DEG C of cryostat；Then by step
（2）The solution shape of preparation is modified lazy propylhomoserin Boc-lys-OMe（Compound 4）It is added dropwise in the mixed system, maintain the temperature at-
10-5 DEG C of reaction 2h, then in room temperature（25-30 DEG C）48 h of lower reaction.Reaction terminates, and sample is filtered, decompression rotation
Solvent is steamed, then column separating purification, eluant, eluent petroleum ether is chromatographed with the dissolving of part methylene chloride solvent（60-90℃）：Third
Ketone=3：1、2：1、3：2 graded series mixed solvents.Finally by the target fraction containing BA-boc-lys-OMe（Compound 5）Enter
Row, which merges, draws dry, is subsequently placed in vacuum drying chamber at 45 DEG C and dries 24 h, prepares the BA-boc- that purity is 99.5%
The g of lys-OMe products 12.98, the % of yield 83.0.
BA-boc-lys-OMe's1H NMR（500 MHz, CDCl3）With1C NMR（500 MHz, CDCl3）And document report
Unanimously；MS：698.2（M+）.
（4）By step（3）The 12.51g BA-boc-lys-OMe of preparation（Compound 5）It is dissolved in 100 mL tetrahydrofurans
（THF）In, add 7.55 mL water（H2O）, then add 1.90g Li2CO3, room temperature（25-30 DEG C）48 h of lower reaction.Reaction
Terminate, the 150 mL saturated common salt aqueous solution is added into reaction solution, then with 50 mL dichloromethane（DCM）Extract 2-3
It is secondary, merge organic DCM phases, with 50 mL washings twice, then use anhydrous Na2SO4It is dried overnight.Filtering, decompression rotation, produces mesh
Mark product betulonic acid-amino acid derivativges BA-boc-lys-OH.Finally with the upper chromatographic column point of part methylene chloride solvent dissolving
From purifying, eluant, eluent dichloromethane：Methanol=12：1、11：1、10：1 graded series mixed solvent.BA-boc- will finally be contained
Lys-OH target fraction merges drawing and done, and is subsequently placed in vacuum drying chamber at 45 DEG C and dries 24 h, prepares purity
For the 99.7 % g of BA-boc-lys-OH products 11.5, the % of yield 93.8.
BA-boc-lys-OH's1H NMR（500 MHz, CDCl3）With1C NMR（500 MHz, CDCl3）And document report
Unanimously；MS：683.2（M+）.
Target product betulonic acid-amino acid derivativges BA-boc-lys-OH total recovery is 68.2 %.
Embodiment 2
（1）The betulinol for weighing 24.00 g is added in 1200 mL tetrahydrofuran solvent, 40 DEG C or so lower heating stirrings 30
Min, is then cooled to -10 DEG C.Then 288.0 g of brand-new Jones reagents are added dropwise to above-mentioned reaction bulb
In.Reaction temperature is maintained at -10 DEG C, maintenance reaction time 4h.After reaction terminates, it is added dropwise 1200 mL's under the conditions of -10 DEG C
Propyl alcohol reagent is quenched.Then proceed to stir 60 min.1200 mL water are finally added dropwise and are stirred for 30 min.Above-mentioned reaction solution is entered
Row decompression rotation, filters out blackish green precipitation.Raffinate is extracted with ethyl acetate at least 3 times, then washes 3 times with saturated common salt, most
After use anhydrous Na2SO4It is dried overnight.Filtering, rotates to obtain light green solid i.e. betulonic acid crude product.By betulonic acid crude product with less
Measure after dichloromethane dissolving, upper chromatography post separation, eluant, eluent petroleum ether（60-90 ℃）：Ethyl acetate=4：1、3：1、2：1 is
Row gradient mixed solvent, merges drawing by the target fraction containing BA and does, be subsequently placed in vacuum drying chamber at 45 DEG C and dry
24 h, prepare the g of betulonic acid product 20.95 that purity is 99.5 %, and yield is 85.0 %.
（2）Weigh lysine derivative Boc-Lys (Fmoc)-OMe（Compound 3）27.50 g, are dissolved in containing quality
In the acetonitrile solvent of the trimethylamine of percentage 15%, room temperature（25-30 ℃）0.5 h of lower reaction.Question response completely, is poured into 200
In mL mixture of ice and water, stirring.Then this mixture is washed with the mixed solvent of 40 mL ethyl acetate and 200 mL petroleum ethers
Once, liquid is divided to discard upper oil phase.Aqueous phase is added after appropriate NaCl, is extracted with ethyl acetate at least 15 times.Finally merge acetic acid
Ethyl ester organic phase, uses anhydrous Na2SO4 is dried overnight.Filtering, decompression rotation obtains the modified lazy of the i.e. DMF containing part of solution shape material
Propylhomoserin Boc-lys-OMe（Compound 4）；
（3）By step（1）The 20.95 g betulonic acids prepared are dissolved in 140 mL anhydrous tetrahydro furans, then add 8.44
G HOAT, 7.27 g DIC and 9.78 mL triethylamine, stir 30 min under the conditions of -10--5 DEG C of cryostat；Then by step
（2）The solution shape of preparation is modified lazy propylhomoserin Boc-lys-OMe（Compound 4）It is added dropwise in the mixed system, maintain the temperature at-
10-5 DEG C of 2 h of reaction, then in room temperature（25-30 DEG C）48 h of lower reaction., can according to the extent of reaction of dehydration condensation
It is properly added DMAP（DMAP）0.56 g.Reaction terminates, and sample is filtered, vacuum rotary steam solvent, then
Column separating purification, eluant, eluent n-hexane are chromatographed with the dissolving of part methylene chloride solvent：Acetone=4：1、3：1、2：1 series ladder
Spend mixed solvent.Finally by the target fraction containing BA-boc-lys-OMe（Compound 5）Merge drawing dry, be subsequently placed in true
24 h are dried in empty drying box at 45 DEG C, the g of BA-boc-lys-OMe products 26.72 that purity is 99.5 % is prepared, receives
The % of rate 83.2.
BA-boc-lys-OMe's1H NMR（500 MHz, CDCl3）With1C NMR（500 MHz, CDCl3）And document report
Unanimously；MS：698.2（M+）
（4）By step（3）The 26.72 g BA-boc-lys-OMe prepared（Compound 5）It is dissolved in 250 mL acetone
（Acetone）In, add 10.58 mL water（H2O）, then add 1.96 g NaOH.Room temperature（25-30 DEG C）Lower reaction 48
h.Reaction terminates, and the 300mL saturated common salt aqueous solution is added into reaction solution, then with 100 mL ethyl acetate（EA）Extraction
2-3 times, merge organic EA phases, with 100 mL washings twice, then use anhydrous Na2SO4It is dried overnight.Filtering, decompression rotation, i.e.,
Obtain target product betulonic acid-amino acid derivativges BA-boc-lys-OH.Finally chromatographed with the dissolving of part methylene chloride solvent
Column separating purification, eluant, eluent dichloromethane：Ethyl acetate=3：1、2：1、1：1 graded series mixed solvent.It will finally contain
BA-boc-lys-OH target fraction merges drawing and done, and being subsequently placed in vacuum drying chamber at 45 DEG C dry 24 h can make
It is standby to obtain the g of BA-boc-lys-OH products 23.70, the % of yield 90.5 that purity is 99.5%.
BA-boc-lys-OH's1H NMR（500 MHz, CDCl3）With1C NMR（500 MHz, CDCl3）And document report
Unanimously；MS：683.2（M+）.
Target product betulonic acid-amino acid derivativges BA-boc-lys-OH total recovery is 64.0 %.
Betulonic acid prepared by the present invention-amino acid derivativges BA-boc-lys-OH, with good water solubility and it is anti-before
Row adenoncus tumor activity.
Claims (3)
1. a kind of synthetic method of betulonic acid-amino acid derivativges, it is characterised in that realize by the following method：
（1）Betulinol is dissolved in organic solvent, Jones reagent is added and is aoxidized, reaction terminates, add quencher quenches；
Then, reaction solution is depressurized and rotated, suction filtration extracts filtrate, washed, dry again through column chromatography for separation, obtain compound 2；It is described
Organic solvent selects acetonitrile, acetone or tetrahydrofuran；
（2）Compound 3 is dissolved in the organic solvent containing the alkaline reagent of weight/mass percentage composition 15%；Question response completely, is poured into
In mixture of ice and water, add non-polar solven or low pole solution carries out a point liquid, remove oil phase；Then aqueous phase is extracted,
Decompression rotation, dry compound 4；The organic solvent selects methanol, ethanol, acetonitrile, acetone, tetrahydrofuran or N, N- dimethyl
Formamide；The alkaline reagent selects ammoniacal liquor or methylamine, dimethylamine, trimethylamine, ethamine, diethylamine or triethylamine solution；
（3）Compound 2 is dissolved in organic solvent, alkaline reagent, condensing agent and dehydrating agent is then added and mixes, add
Compound 4 is reacted, and obtains compound 5；Reaction terminates, and sample is post-processed and column chromatographic isolation and purification；
The organic solvent selects methanol, ethanol, acetonitrile, acetone, tetrahydrofuran, N,N-dimethylformamide, dichloromethane, chloroform
Or dimethyl sulfoxide (DMSO)；
The alkaline reagent selects methylamine, dimethylamine, trimethylamine, ethamine, diethylamine or triethylamine solution；
The condensing agent selects I-hydroxybenzotriazole, N- hydroxyls -7- azepines BTA or BTA -1- bases epoxide three
（Dimethylamino）Phosphorus hexafluorophosphate；
The dehydrating agent selects N, N'- Dicyclohexylcarbodiimides, N, N'- DICs or 1- ethyls-(3- dimethyl
Aminopropyl) carbodiimide hydrochloride；
（4）Compound 5 is dissolved in organic solvent miscible with water, first adds water, added basic hydrolysis reagent and carry out instead
Should；Reaction terminates, and product is post-processed and column chromatographic isolation and purification obtains target product；
The organic solvent selects methanol, ethanol, acetone, tetrahydrofuran；The basic hydrolysis reagent selects water lithium hydroxide, hydrogen-oxygen
Change potassium, sodium hydroxide, lithium carbonate, potassium carbonate, sodium carbonate, sodium acid carbonate or saleratus.
2. the synthetic method of betulonic acid-amino acid derivativges as claimed in claim 1, it is characterised in that step（1）Middleization
The betulinol of compound 1：The mass/volume ratio of organic solvent is 1：50, unit g/mL；The mass/volume of betulinol and Jones reagent
Than for 1：12, unit g/mL, reaction temperature are -10 DEG C.
3. the synthetic method of betulonic acid-amino acid derivativges as claimed in claim 1, it is characterised in that step（3）Middleization
Compound 4 reacts 2 h under the conditions of cryostat-10-5 DEG C are selected when adding, then reacts 48 h at room temperature at 25-30 DEG C.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111875570A (en) * | 2020-07-31 | 2020-11-03 | 郑州师范学院 | Synthetic method of fluorine-containing carboxylic acid flavone-amino acid derivative |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101083997A (en) * | 2004-09-10 | 2007-12-05 | 康乃尔研究基金会有限公司 | Betulinol derivatives as anti-cancer agents |
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| BRIJ B. SAXENA等: "Boc-lysinated-betulonic acid: A potent, anti-prostate cancer agent", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
| YUICHI MASUDA等: "Synthesis of (2S,3R,4R)-3,4-dihydroxyarginine and its inhibitory activity against nitric oxide synthase", 《TETRAHEDRON》 * |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111875570A (en) * | 2020-07-31 | 2020-11-03 | 郑州师范学院 | Synthetic method of fluorine-containing carboxylic acid flavone-amino acid derivative |
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