CN106986912B - A kind of synthetic method of betulonic acid-amino acid derivativges - Google Patents
A kind of synthetic method of betulonic acid-amino acid derivativges Download PDFInfo
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Abstract
The invention discloses a kind of synthetic methods 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, solves the problems, such as that there is lack of raw materials for betulonic acid needed for preparing wooden ketone acid-amino acid derivativges；By betulonic acid and modified lysine, dehydration condensation is carried out, hydrolysis prepares betulonic acid-amino acid derivativges, shortens reaction step, substantially increases the yield of product, and avoid catalytic hydrogenation reaction.Meanwhile it being synthetically prepared the high income of one of betulonic acid-amino acid derivativges raw material betulonic acid, and up to 83% or more, purity is high, up to 99.5% or more.The betulonic acid being synthetically prepared out-amino acid derivativges good water solubility, anti-prostate tumor activity is strong, has good application value to the drug for developing novel anti-prostate tumor.
Description
Technical field
The invention belongs to organic chemistry pharmaceutical synthesis fields, and in particular to a kind of synthesis of betulonic acid-amino acid derivativges
Method.
Background technique
Currently, tumour especially malignant tumour is still to endanger one of the common disease of human health and life, and only in China
Just there is 1 to die of malignant tumour in every 4-5 died.He result of investigation is shown, in cause of the death ranking, mortality of malignant tumors
It accounts for first of city dweller's cause of death, third is occupied in rural resident.Although recent years, anti-tumor drug has quickly
Development and breakthrough, newtype drug also continuously emerges.But the treatment for tumor of prostate, so far, it has not been found that
Effective specific drug.
Four major class can be divided into the source of anti-tumor drug: microbe-derived medicine (antitumor antibiotics), chemical synthesis
Medicine, biotechnology medicine, plant origin medicine.It include planting wherein applied in clinical anti-tumor drug about 1/3 from plant
The original shape ingredient and its derivative of object itself, wherein including the plant structures such as taxanes, lignanoids, alkaloids and terpene
Type, and terpene divides sequiterpene, diterpene, triterpene and triterpene glycoside.Betulinol is the pentacyclic triterpene alkenes for having C-30 skeleton
Object is closed, the structure of lupane is integrally maintained, is native compound very abundant, 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, content has reached 25% or so of bark dry weight.
Show according to the study: betulinol and its derivative betulinic acid especially betulonic acid all have clearing heat and detoxicating, Adjust-blood lipid,
Improve immunity, anti-inflammatory, improve hair gloss, promote natural on-off cycles of hair growth, is anti-inflammatory, anti-dysentery, antipathogen, prostaglandin E2 and
The effects of nitric oxide production inhibition body.Importantly, they show in terms of AntiHIV1 RT activity and antitumor isoreactivity than previous
Target-oriented drug is stronger, mechanism of action less lower, the smaller characteristic of toxic side effect with, immunosuppressive action.Therefore, for
The close attention of the research of betulinol and its this kind of newtype drug of derivative has gradually received drug research person.But birch
The development and application and clinical research of ketone acid, which receive, significantly to be limited, the reason is that its water solubility is very poor, it is extremely difficult to and it is soluble in water,
So that its anticancer activity 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, high bioactivity, especially anti-tumor activity and good water solubility are developed into treatment forefront
The specific drug of adenoncus tumor, 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, State of Zhao .108-114
(2007), Zhang little Li etc., the documents such as Beijing Forestry University journal .33 (1): 134-138 (2011), which report, uses betulonic acid
Make raw material and related amino acid reaction has synthesized betulonic acid-amino acid derivativges, some documents are also inhibiting tumour thin it
The activity aspect of intracellular growth 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)；It is reported in the documents such as Saxena etal.US2009/0176753A1 and Chinese patent CN 201280031564.0
Road betulonic acid and lysine reaction synthesis betulonic acid-amino acid derivativges related fields research, to its antitumor work
Property has also carried out certain research.But the above reaction in relation to betulonic acid and lysine is to be by three six small steps of big step
Column chemical reactive synthesis, reaction step is long, and yield is low, and has catalytic hydrogenation reaction.For convenient for industrialized developing and application, mesh
Preceding urgent need improves its preparation process.
Summary of the invention
A kind of it is an object of that present invention to provide reaction steps short, high income betulonic acid-amino acid derivativges synthesis side
Method is convenient for industrial application.
Purpose to realize the present invention, the present invention carry out dehydration condensation using betulonic acid and modified lysine as raw material,
Further hydrolysis prepares betulonic acid-amino acid derivativges.It is synthesized especially by following method:
(1) it is that betulinol is dissolved in organic solvent by compound 1, Jones (Jones) reagent is added and aoxidizes.Reaction
Terminate, quencher quenches are added.Then, reaction solution is depressurized and is rotated, filtered, extract filtrate, washed, is dry again through column chromatography point
From obtaining compound 2；The organic solvent selects acetonitrile, acetone, tetrahydrofuran etc..
It (2) is that lysine derivative Boc-Lys (Fmoc)-OMe is dissolved in containing mass percentage 15% by compound 3
In the organic solvent of alkaline reagent；To fully reacting, pour into mixture of ice and water, be added nonpolar solvent or low pole solution into
Oil removing phase is gone in row liquid separation.Then water phase is extracted, decompression rotation, the compound 4 of dry good water solubility is Boc-lys-
OMe；The organic solvent selects methanol, ethyl alcohol, acetonitrile, acetone, tetrahydrofuran, N,N-dimethylformamide etc..The alkalinity examination
Ammonium hydroxide 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 is mixed,
Compound 4 is added to react, obtains compound 5 i.e. betulonic acid-amino acid derivativges intermediate B A-boc-lys-OMe.Reaction knot
Beam carries out post-processing and column chromatographic isolation and purification to sample.
The organic solvent select methanol, ethyl alcohol, acetonitrile, acetone, tetrahydrofuran, N,N-dimethylformamide, methylene chloride,
Chloroform or dimethyl sulfoxide.
The alkaline reagent selects methylamine, dimethylamine, trimethylamine, ethamine, diethylamine, triethylamine solution etc..
The condensing agent selects I-hydroxybenzotriazole (HOBT), N- hydroxyl -7- azepine benzotriazole (HOAT), benzo three
Three (dimethylamino) phosphorus hexafluorophosphate (BOP) of nitrogen azoles -1- base oxygroup etc..
The dehydrating agent choosing is mainly the related substances of Carbodiimides, such as N, N'- Dicyclohexylcarbodiimide
(DCC), N, N'- diisopropylcarbodiimide (DIC), 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride
(EDCHCl) etc.；According to the extent of reaction situation of dehydration condensation, the efficient catalytic that can be catalyzed the reaction can be properly added
Agent 4-dimethylaminopyridine (DMAP).
(4) compound 5 is dissolved in organic solvent miscible with water, water is first added, add basic hydrolysis reagent into
Row reaction.Reaction terminates, and carries out post-processing to product and column chromatographic isolation and purification obtains target product betulonic acid-amino acid and spreads out
Biological BA-boc-lys-OH.
The organic solvent selects methanol, ethyl alcohol, acetone, tetrahydrofuran.
The basic hydrolysis reagent select water lithium hydroxide, potassium hydroxide, sodium hydroxide, lithium carbonate, potassium carbonate, sodium carbonate,
Sodium bicarbonate, saleratus etc..
L is used in step (1)9(34) orthogonal, optimal processing parameter is betulinol: the ratio of organic solvent is
The ratio of 1:50 (g:mL), betulinol and Jones reagent is 1:12 (g:mL), and reaction temperature is -10 DEG C, reaction time 4h.
When compound 4 is added in step (3) it is-10-5 DEG C of cryostat preferred under the conditions of react 2h, then at room temperature (25-30 DEG C)
Lower reaction 48h.
Innovative point of the present invention and advantage are: with betulinol cheap and easy to get, (betulinol contains this method in Japanese birch bark
25%) amount is up to synthetically prepared betulonic acid, solving betulonic acid needed for preparing wooden ketone acid-amino acid derivativges, there is lack of raw materials
Problem, meanwhile, the high income of the betulonic acid of synthesis, up to 83% or more, purity is high, up to 99.5% or more.By betulonic acid and
Modified lysine carries out dehydration condensation, and hydrolysis prepares betulonic acid-amino acid derivativges, shortens reaction step
Suddenly, the yield (total recovery >=64.0%) of product is substantially increased, and avoids catalytic hydrogenation reaction.The birch being synthetically prepared out
Ketone acid-amino acid derivativges good water solubility, anti-prostate tumor activity is strong, has to the drug for developing novel anti-prostate tumor
Good application value.
Detailed description of the invention
Fig. 1 is the HPLC map of betulonic acid product prepared by the present invention；
Fig. 2 is the HPLC map of betulonic acid standard items；
Fig. 3 is the mass spectrogram of betulonic acid product prepared by the present invention.
Specific embodiment
For the present invention is better described, specific embodiment is as follows:
Embodiment 1
(1) betulinol for weighing 12.00g is added in the acetone solvent of 600mL, 40 DEG C or so lower heating stirring 30min,
It is then cooled to -10 DEG C.Then the Jones reagent of the 144.0g of brand-new is added dropwise in above-mentioned reaction flask.Reaction
Temperature is maintained at -10 DEG C, maintains reaction time 4h.After reaction, the ethanol reagent that 600mL is added dropwise under the conditions of -10 DEG C is sudden
It goes out.Then proceed to stirring 60min.600mL water is finally added dropwise and is stirred for 30min.Decompression rotation is carried out to above-mentioned reaction solution, is filtered out
Blackish green precipitating.Raffinate tetrahydrofuran extracts at least 3 times, is then washed 3 times with saturated common salt, finally uses anhydrous Na2SO4It is dry
It is dry overnight.Filtering, rotates to obtain light green solid i.e. betulonic acid crude product.The a small amount of methylene chloride of betulonic acid crude product is dissolved
Afterwards, upper chromatography post separation, eluant, eluent methylene chloride: ethyl acetate=2:1,1:1,1:2 graded series mixed solvent will contain
The target fraction of betulonic acid merges drawing and does, and is subsequently placed in vacuum oven drying at 45 DEG C and for 24 hours, purity is prepared
For 99.5% betulonic acid product 10.80g, yield 87.6%.
(2) lysine derivative Boc-Lys (Fmoc)-OMe (compound 3) 13.75g is weighed to be dissolved in containing quality percentage
Than the N of 15% triethylamine, in N- dimethylformamide (DMF) solvent, 0.5h is reacted under room temperature (25-30 DEG C).To fully reacting,
It is poured into 200mL mixture of ice and water, stirs.Then by the mixed of this mixture 20mL ethyl acetate and 100mL petroleum ether
Bonding solvent washed once, and liquid separation discards upper oil phase.After appropriate NaCl is added in water phase, it is extracted with ethyl acetate at least 15 times.Most
Combined ethyl acetate organic phase afterwards uses anhydrous Na2SO4 is dried overnight.Filtering, decompression rotation, obtains solution shape substance and contains part
The modified lazy propylhomoserin (compound 4) of the Boc-lys-OMe of DMF；
(3) 10.20g betulonic acid prepared by step (1) is dissolved in 70mL anhydrous propanone, 13.10g is then added
The trimethylamine of BOP, 4.94g EDCHCl and 4.67mL stir 30min under the conditions of -10--5 DEG C of cryostat；Then by step (2)
The solution shape of preparation modified lazyness propylhomoserin Boc-lys-OMe (compound 4) is added dropwise in the mixed system, maintains the temperature at-10-5
DEG C reaction 2h, then react 48h under room temperature (25-30 DEG C).Reaction terminates, and is filtered to sample, vacuum rotary steam solvent,
Then column separating purification is chromatographed in the dissolution of part methylene chloride solvent, eluant, eluent is with petroleum ether (60-90 DEG C): acetone=3:1,
2:1,3:2 graded series mixed solvent.The target fraction (compound 5) containing BA-boc-lys-OMe is finally merged into drawing
It is dry, it is subsequently placed in vacuum oven drying at 45 DEG C and for 24 hours, the BA-boc-lys-OMe product that purity is 99.5% is prepared
12.98g yield 83.0%.
BA-boc-lys-OMe's1H NMR (500MHz, CDCl3) and1C NMR (500MHz, CDCl3) and document report one
It causes；MS:698.2 (M+)。
(4) 12.51g BA-boc-lys-OMe (compound 5) prepared by step (3) is dissolved in 100mL tetrahydrofuran
(THF) in, 7.55mL water (H is added2O), 1.90g Li is then added2CO3, 48h is reacted under room temperature (25-30 DEG C).Reaction knot
The saturated common salt aqueous solution of 150mL is added into reaction solution for beam, is then extracted 2-3 times with 50mL methylene chloride (DCM), closes
And then organic DCM phase twice with 50mL washing uses anhydrous Na2SO4It is dried overnight.Filtering, decompression rotation is to get target product
Betulonic acid-amino acid derivativges BA-boc-lys-OH.It is finally pure with chromatography post separation in the dissolution of part methylene chloride solvent
Change, eluant, eluent methylene chloride: methanol=12:1,11:1,10:1 graded series mixed solvent.BA-boc- will finally be contained
The target fraction of lys-OH merges drawing and does, and being subsequently placed in vacuum oven drying at 45 DEG C, for 24 hours, purity, which is prepared, is
99.7% BA-boc-lys-OH product 11.5g, yield 93.8%.
BA-boc-lys-OH's1H NMR (500MHz, CDCl3) and1C NMR (500MHz, CDCl3) and document report one
It causes；MS:683.2 (M+)。
Target product betulonic acid-amino acid derivativges BA-boc-lys-OH total recovery is 68.2%.
Embodiment 2
(1) betulinol for weighing 24.00g is added in the tetrahydrofuran solvent of 1200mL, 40 DEG C or so lower heating stirrings
30min is then cooled to -10 DEG C.Then the Jones reagent of the 288.0g of brand-new is added dropwise to above-mentioned reaction flask
In.Reaction temperature is maintained at -10 DEG C, maintains reaction time 4h.After reaction, the third of 1200mL is added dropwise under the conditions of -10 DEG C
The quenching of alcohol reagent.Then proceed to stirring 60min.1200mL water is finally added dropwise and is stirred for 30min.Above-mentioned reaction solution is depressurized
Rotation, filters out blackish green precipitating.Raffinate is extracted with ethyl acetate at least 3 times, is then washed 3 times with saturated common salt, finally uses nothing
Water Na2SO4It is dried overnight.Filtering, rotates to obtain light green solid i.e. betulonic acid crude product.By a small amount of dichloro of betulonic acid crude product
After methane dissolution, upper chromatography post separation, eluant, eluent is with petroleum ether (60-90 DEG C): ethyl acetate=4: 1,3: 1,2: 1 graded series
Target fraction containing BA is merged drawing and done by mixed solvent, is subsequently placed in vacuum oven drying at 45 DEG C and for 24 hours, is made
The standby betulonic acid product 20.95g for obtaining purity and being 99.5%, yield 85.0%.
(2) lysine derivative Boc-Lys (Fmoc)-OMe (compound 3) 27.50g is weighed, is dissolved in containing quality hundred
Divide in the acetonitrile solvent than 15% trimethylamine, reacts 0.5h under room temperature (25-30 DEG C).To fully reacting, it is poured into 200mL ice
In aqueous mixtures, stirring.Then this mixture washed once with the mixed solvent of 40mL ethyl acetate and 200mL petroleum ether,
Liquid separation discards upper oil phase.After appropriate NaCl is added in water phase, it is extracted with ethyl acetate at least 15 times.Last combined ethyl acetate has
Machine phase, uses anhydrous Na2SO4 is dried overnight.Filtering, decompression rotation obtain the modified lazy propylhomoserin of the i.e. DMF containing part of solution shape substance
Boc-lys-OMe (compound 4)；
(3) 20.95g betulonic acid prepared by step (1) is dissolved in 140mL anhydrous tetrahydro furan, is then added
The triethylamine of 8.44g HOAT, 7.27g DIC and 9.78mL stir 30min under the conditions of -10--5 DEG C of cryostat；Then by step
(2) the solution shape prepared modified lazyness propylhomoserin Boc-lys-OMe (compound 4) is added dropwise in the mixed system, maintain the temperature at-
10-5 DEG C of reaction 2h, then react 48h under room temperature (25-30 DEG C).It, can be appropriate according to the extent of reaction of dehydration condensation
Add 4-dimethylaminopyridine (DMAP) 0.56g.Reaction terminates, and is filtered to sample, then vacuum rotary steam solvent uses part
Column separating purification is chromatographed in dichloromethane solvent dissolution, eluant, eluent n-hexane: acetone=4:1,3:1,2:1 graded series mixing
Solvent.The target fraction (compound 5) containing BA-boc-lys-OMe is finally merged drawing to do, is subsequently placed in vacuum drying
For 24 hours, the BA-boc-lys-OMe product 26.72g that purity is 99.5%, yield 83.2% is prepared in drying at 45 DEG C in case.
BA-boc-lys-OMe's1H NMR (500MHz, CDCl3) and1C NMR (500MHz, CDCl3) and document report one
It causes；MS:698.2 (M+)
(4) 26.72g BA-boc-lys-OMe (compound 5) prepared by step (3) is dissolved in 250mL acetone
(Acetone) in, 10.58mL water (H is added2O), 1.96g NaOH is then added.48h is reacted under room temperature (25-30 DEG C).Instead
It should terminate, the saturated common salt aqueous solution of 300mL is added into reaction solution, then extract 2-3 with 100mL ethyl acetate (EA)
It is secondary, merge organic EA phase, twice with 100mL washing, then uses anhydrous Na2SO4It is dried overnight.Filtering, decompression rotation is to get mesh
Mark product betulonic acid-amino acid derivativges BA-boc-lys-OH.Finally upper chromatographic column point is dissolved with part methylene chloride solvent
From purifying, eluant, eluent methylene chloride: ethyl acetate=3:1,2:1,1:1 graded series mixed solvent.BA- will finally be contained
The target fraction of boc-lys-OH merges drawing and does, and being subsequently placed in vacuum oven drying at 45 DEG C can be prepared into for 24 hours
The BA-boc-lys-OH product 23.70g for being 99.5% to purity, yield 90.5%.
BA-boc-lys-OH's1H NMR (500MHz, CDCl3) and1C NMR (500MHz, CDCl3) and document report one
It causes；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, before there is good water solubility and resist
Column adenoncus tumor activity.
Claims (1)
1. a kind of synthetic method of betulonic acid-amino acid derivativges, which is characterized in that realize by the following method:
(1) betulinol is dissolved in organic solvent, Jones reagent is added and is aoxidized, reaction terminates, and quencher quenches are added；
Then, reaction solution is depressurized and is rotated, filtered, extract filtrate, washed, is dry again through column chromatography for separation, obtaining compound 2；It is described
Organic solvent selects acetonitrile, acetone or tetrahydrofuran；
(2) compound 3 is dissolved in the organic solvent containing 15% alkaline reagent of mass percentage；To fully reacting,
Enter in mixture of ice and water, nonpolar solvent is added or low pole solution carries out liquid separation, goes oil removing phase；Then water phase is extracted
It takes, decompression rotation, dry compound 4；The organic solvent selects methanol, ethyl alcohol, acetonitrile, acetone, tetrahydrofuran or N, N- bis-
Methylformamide；The alkaline reagent selects ammonium hydroxide 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 is mixed, is added
Compound 4 reacts, and obtains compound 5；Reaction terminates, and carries out post-processing and column chromatographic isolation and purification to sample；
The organic solvent selects methanol, ethyl alcohol, acetonitrile, acetone, tetrahydrofuran, N,N-dimethylformamide, methylene chloride, chloroform
Or dimethyl sulfoxide；
The alkaline reagent selects methylamine, dimethylamine, trimethylamine, ethamine, diethylamine or triethylamine solution；
The condensing agent selects I-hydroxybenzotriazole, N- hydroxyl -7- azepine benzotriazole or benzotriazole -1- base oxygroup three
(dimethylamino) phosphorus hexafluorophosphate；
The dehydrating agent selects N, N'- Dicyclohexylcarbodiimide, N, N'- diisopropylcarbodiimide or 1- ethyl-(3- dimethyl
Aminopropyl) carbodiimide hydrochloride；
(4) compound 5 is dissolved in organic solvent miscible with water, water is first added, added basic hydrolysis reagent and carry out instead
It answers；Reaction terminates, and carries out post-processing to product and column chromatographic isolation and purification obtains target product；
The organic solvent selects methanol, ethyl alcohol, acetone, tetrahydrofuran；The basic hydrolysis reagent selects water lithium hydroxide, hydroxide
Potassium, sodium hydroxide, lithium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate or saleratus；
1 betulinol of compound in step (1): the mass/volume ratio of organic solvent is 1:50, unit g/mL；Betulinol and Jones
The mass/volume ratio of reagent is 1:12, and unit g/mL, reaction temperature is -10 DEG C；
2h is reacted under the conditions of selecting 5 DEG C of cryostat-10-when compound 4 is added in step (3), then is reacted at room temperature at 25-30 DEG C
48h。
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| 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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| 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 |
Non-Patent Citations (3)
| Title |
|---|
| Boc-lysinated-betulonic acid: A potent, anti-prostate cancer agent;Brij B. Saxena等;《Bioorganic & Medicinal Chemistry》;20060915;第14卷(第18期);第6349-6358页 |
| Synthesis of (2S,3R,4R)-3,4-dihydroxyarginine and its inhibitory activity against nitric oxide synthase;Yuichi Masuda等;《Tetrahedron》;20160908;第72卷(第36期);第5602-5611页 |
| 桦木醇一步氧化法合成桦木酮酸的研究;赵俊宏等;《河南科学》;20160801;第34卷(第7期);第1049-1053页 |
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