CN109824748A - B- norcholesterol oxidized derivatives and its synthetic method and application - Google Patents
B- norcholesterol oxidized derivatives and its synthetic method and application Download PDFInfo
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- CN109824748A CN109824748A CN201910234252.3A CN201910234252A CN109824748A CN 109824748 A CN109824748 A CN 109824748A CN 201910234252 A CN201910234252 A CN 201910234252A CN 109824748 A CN109824748 A CN 109824748A
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Abstract
The present invention provides a kind of B- norcholesterol oxidized derivatives, the structural formulas of the compound are as follows:Wherein, R CH3、CH3CH2CH2、CH3CH2CH2CH2、
Description
Technical field
The present invention relates to compound synthesis technical fields, it is more particularly related to B- norcholesterol oxidization deriving
Object and its synthetic method and application.
Background technique
Cholesterol is human body important component, and human body can release ozone in the state of there are certain inflammation, and smelly
Oxygen can make the cholesterol in human body that ozonisation fracture occur and form the disconnected cholesterol of B-, and B- breaks cholesterol can further occurrence ring
Change reaction formed have [6-5-6-5]-condensed cyclic structure B- norcholesterol, B- norcholesterol under the action of human-body biological enzyme,
Oxidation occurs respectively or reduction reaction forms the disconnected cholesterol oxidation product of B- and reduzate.Have at present and chemistry is carried out to cholesterol
The correlative study for modifying transformation, is studied but without the compound to B- norcholesterol oxidized derivatives.
Summary of the invention
It is an object of the invention to solve the above problems, and provide the advantages of at least will be described later.
It is a still further object of the present invention to provide a kind of B- norcholesterol oxidized derivatives, the structural formulas of the compound are as follows:
Wherein, R CH3、CH3CH2CH2、CH3CH2CH2CH2、One of.
The present invention also provides the synthetic methods of above-mentioned B- norcholesterol oxidized derivatives, comprising the following steps:
S1, the first compound, the structural formula of the first compound are obtained after acylation reaction is occurred for cholesterol and RCOCl are as follows:
S2, the first compound is obtained to second compound, the structural formula of second compound after ozonization are as follows:
S3, by second compound and neutral alumina reactive aluminum, obtain third compound, third through intramolecular aldol condensation
Close the structural formula of object are as follows:
S4, by after third compound oxidation up to B- norcholesterol oxidized derivatives.
Preferably, cholesterol is dissolved in dichloromethane in S1 by the synthetic method of the B- norcholesterol oxidized derivatives
In alkane, triethylamine, RCOCl is then added, after temperature is to react at 20~25 DEG C, separates up to the first compound；Wherein, gallbladder
Sterol, RCOCl, methylene chloride, triethylamine molal volume ratio be 0.9~1.1mmol:1.9~2.1 mmol:18~22ml:
0.8~1.2ml.
Preferably, the first compound is dissolved in two in S2 by the synthetic method of the B- norcholesterol oxidized derivatives
In chloromethanes, methanol is then added, is passed through O3, it is to react 2~4h at -80~-60 DEG C in temperature, dimethyl sulphide is then added,
The reaction was continued 4~6h, decompression are spin-dried for up to second compound；Wherein, first compound, methylene chloride, methanol, dimethyl sulphide
Molal volume ratio is 1.9~2.1mmol:28~32ml:4~6ml:4~6ml.
Preferably, second compound is dissolved in benzene in S3 by the synthetic method of the B- norcholesterol oxidized derivatives
In, neutral alumina is added, after the reaction was completed, separates up to third compound；Wherein second compound, benzene, neutral alumina
Molal weight ratio be 1.4~1.6mmol:18~20g:9~11mg.
Preferably, third compound is dissolved in S4 and containing by the synthetic method of the B- norcholesterol oxidized derivatives
In the tetrahydrofuran for having 2- methyl-2-butene, be then added in the water containing sodium chlorite and sodium dihydrogen phosphate, in temperature be 30
It reacts, is separated up to B- norcholesterol oxidized derivatives at~40 DEG C；Wherein, third compound, 2- methyl-2-butene, sub- chlorine
Sour sodium, sodium dihydrogen phosphate, tetrahydrofuran, water molal volume ratio be 0.09~0.11mmol:4.8~5.2mmol:0.8~1.1
Mmol:0.6~0.8mmol:1~1.2ml:0.9~1.1ml.
The B- norcholesterol oxidized derivatives application in preparation of anti-tumor drugs.
The synthetic method route of B- norcholesterol oxidized derivatives of the invention is as follows:
The further object of the present invention is to provide above compound application in preparation of anti-tumor drugs.
The present invention includes at least following effect:
1, B- norcholesterol oxidization deriving compounds of the invention, to human breast cancer cell, human milk gland ductal carcinoma cells,
Proliferation of Human Ovarian Cell has significant inhibition growth of tumour cell cultivation effect, can be used as pharmaceutical intermediate or medicinal application in not
Same drug manufacture and purposes.
Further advantage, target and feature of the invention will be partially reflected by the following instructions, and part will also be by this
The research and practice of invention and be understood by the person skilled in the art.
Specific embodiment
The present invention will be further described in detail below with reference to the embodiments, to enable those skilled in the art referring to specification
Text can be implemented accordingly.
It should be noted that experimental method described in following embodiments is unless otherwise specified conventional method, institute
Reagent and material are stated, unless otherwise specified, is commercially obtained.
Embodiment 1
S1, the first compound, the structural formula of the first compound are obtained after acylation reaction is occurred for cholesterol and RCOCl are as follows:R is CH3；
S2, the first compound is obtained to second compound, the structural formula of second compound after ozonization are as follows:
S3, by second compound and neutral alumina reactive aluminum, obtain third compound, third through intramolecular aldol condensation
Close the structural formula of object are as follows:
S4, by after third compound oxidation up to B- norcholesterol oxidized derivatives.
Cholesterol is dissolved in methylene chloride in S1, then by the synthetic method of the B- norcholesterol oxidized derivatives
Triethylamine, CH is added3COCl, is to react at 20 DEG C in temperature, and TLC tracking reaction stops reaction after raw material, separates up to the
One compound；Wherein, cholesterol, RCOCl, methylene chloride, triethylamine molal volume ratio be 1mmol:2mmol:20ml:1ml.
Wherein, separation, which is specifically included, carried out thick column with ethyl acetate, is evaporated under reduced pressure away extra ethyl acetate and methylene chloride, uses
Methylene chloride dissolution, is washed with saturated sodium bicarbonate solution, saturated sodium chloride solution respectively, is successively extracted three times, is merged organic
Phase, crude product column chromatography for separation (mobile phase: ethyl acetate: petroleum ether=1:10), obtaining target product is the first compound.
First compound is dissolved in methylene chloride in S2 by the synthetic method of the B- norcholesterol oxidized derivatives,
Then methanol is added, is passed through O3, it is that 2h is reacted at -80 DEG C in temperature, TLC tracking is reacted, and stops being passed through O after no raw material point3, so
After be added dimethyl sulphide, TLC tracking reaction stops reaction after without obvious raw material, and decompression is spin-dried for up to second compound；Its
In, the first compound, methylene chloride, methanol, dimethyl sulphide molal volume ratio be 2mmol:30ml:5ml:5ml.
Second compound is dissolved in benzene in S3, in addition by the synthetic method of the B- norcholesterol oxidized derivatives
Property aluminium oxide, TLC tracking reaction stops reaction after no raw material point, separates up to third compound；Wherein second compound, benzene,
The molal weight ratio of neutral alumina is 1.5mmol:18g:10mg.When separation, thick column was carried out to product with ethyl acetate, was subtracted
Pressure steams solvent, and crude product column chromatography for separation (mobile phase: ethyl acetate: petroleum ether=1:5) is to get third compound.
Third compound is dissolved in containing 2- methyl-in S4 by the synthetic method of the B- norcholesterol oxidized derivatives
It in the tetrahydrofuran of 2- butylene, is then added in the water containing sodium chlorite and sodium dihydrogen phosphate, is to be reacted at 30 DEG C in temperature,
TLC tracking reaction, after reaction, is removed under reduced pressure solvent, crude product column chromatography for separation to obtain the final productWherein, third compound, 2- methyl-2-butene, sodium chlorite, sodium dihydrogen phosphate, four
Hydrogen furans, water molal volume ratio be 0.1mmol:5mmol:1mmol:0.7mmol:1ml:1ml.The property and core of the derivative
Magnetic data are as follows: m.p.196~201 DEG C1H NMR(CDCl3, 300MHz) and δ: 0.70 (3H, S, C18-H), 0.86 (3H, d, C26-
C),0.87(3H,d, C27-C),0.91(3H,d,C21-H),0.97(3H,s,C19-H),2.06(3H,s,CH3),5.08
(1H,m,OH).13C NMR(CDCl3, 75MHz) and δ: 176.86 (COOH), 169.98 (C=O)
Embodiment 2
S1, the first compound, the structural formula of the first compound are obtained after acylation reaction is occurred for cholesterol and RCOCl are as follows:R is CH3CH2CH2；
S2, the first compound is obtained to second compound, the structural formula of second compound after ozonization are as follows:
S3, by second compound and neutral alumina reactive aluminum, obtain third compound, third through intramolecular aldol condensation
Close the structural formula of object are as follows:
S4, by after third compound oxidation up to B- norcholesterol oxidized derivatives.
Cholesterol is dissolved in methylene chloride in S1, then by the synthetic method of the B- norcholesterol oxidized derivatives
Triethylamine, CH is added3COCl, is to react at 20 DEG C in temperature, and TLC tracking reaction stops reaction after raw material, separates up to the
One compound；Wherein, cholesterol, RCOCl, methylene chloride, triethylamine molal volume ratio be 1mmol:2mmol:20ml:
1ml.Wherein, separation, which is specifically included, carried out thick column with ethyl acetate, was evaporated under reduced pressure away extra ethyl acetate and dichloromethane
Alkane is dissolved with methylene chloride, is washed respectively with saturated sodium bicarbonate solution, saturated sodium chloride solution, is successively extracted three times, is merged
Organic phase, crude product column chromatography for separation (mobile phase: ethyl acetate: petroleum ether=1:10), obtaining target product is the first change
Close object.
First compound is dissolved in methylene chloride in S2 by the synthetic method of the B- norcholesterol oxidized derivatives,
Then methanol is added, is passed through O3, it is that 2h is reacted at -80 DEG C in temperature, TLC tracking is reacted, and stops being passed through O after no raw material point3, so
After be added dimethyl sulphide, TLC tracking reaction stops reaction after without obvious raw material, and decompression is spin-dried for up to second compound；Its
In, the first compound, methylene chloride, methanol, dimethyl sulphide molal volume ratio be 2mmol:30ml:5ml:5ml.
Second compound is dissolved in benzene in S3, in addition by the synthetic method of the B- norcholesterol oxidized derivatives
Property aluminium oxide, TLC tracking reaction stops reaction after no raw material point, separates up to third compound；Wherein second compound, benzene,
The molal weight ratio of neutral alumina is 1.5mmol:18g:10mg.When separation, thick column was carried out to product with ethyl acetate, was subtracted
Pressure steams solvent, and crude product column chromatography for separation (mobile phase: ethyl acetate: petroleum ether=1:5) is to get third compound.
Third compound is dissolved in containing 2- methyl-in S4 by the synthetic method of the B- norcholesterol oxidized derivatives
It in the tetrahydrofuran of 2- butylene, is then added in the water containing sodium chlorite and sodium dihydrogen phosphate, is to be reacted at 30 DEG C in temperature,
TLC tracking reaction, after reaction, is removed under reduced pressure solvent, crude product column chromatography for separation to obtain the final productWherein, third compound, 2- methyl-2-butene, sodium chlorite, di(2-ethylhexyl)phosphate
Hydrogen sodium, tetrahydrofuran, water molal volume ratio be 0.1mmol:5mmol:1mmol:0.7mmol:1ml:1ml.The derivative
Property and nuclear magnetic data are as follows: m.p.90~92 DEG C1H NMR(CDCl3, 300MHz) and δ: 0.70 (3H, S, C18-H), 0.85 (3H,
D, C26-C), 0.88 (3H, d, C27-C), 0.9-0.94 (6H, m, C21-H and CH3), 0.97 (3H, s, C19-H), 5.08
(1H,m,OH).13C NMR(CDCl3, 75MHz) and δ: 176.60 (COOH), 172.77 (C=O)
Embodiment 3
S1, the first compound, the structural formula of the first compound are obtained after acylation reaction is occurred for cholesterol and RCOCl are as follows:R is CH3CH2CH2CH2；
S2, the first compound is obtained to second compound, the structural formula of second compound after ozonization are as follows:
S3, by second compound and neutral alumina reactive aluminum, obtain third compound, third through intramolecular aldol condensation
Close the structural formula of object are as follows:
S4, by after third compound oxidation up to B- norcholesterol oxidized derivatives.
Cholesterol is dissolved in methylene chloride in S1, then by the synthetic method of the B- norcholesterol oxidized derivatives
Triethylamine, CH is added3COCl, is to react at 20 DEG C in temperature, and TLC tracking reaction stops reaction after raw material, separates up to the
One compound；Wherein, cholesterol, RCOCl, methylene chloride, triethylamine molal volume ratio be 1mmol:2mmol:20ml:1ml.
Wherein, separation, which is specifically included, carried out thick column with ethyl acetate, is evaporated under reduced pressure away extra ethyl acetate and methylene chloride, uses
Methylene chloride dissolution, is washed with saturated sodium bicarbonate solution, saturated sodium chloride solution respectively, is successively extracted three times, is merged organic
Phase, crude product column chromatography for separation (mobile phase: ethyl acetate: petroleum ether=1:10), obtaining target product is the first compound.
First compound is dissolved in methylene chloride in S2 by the synthetic method of the B- norcholesterol oxidized derivatives,
Then methanol is added, is passed through O3, it is that 2h is reacted at -80 DEG C in temperature, TLC tracking is reacted, and stops being passed through O after no raw material point3, so
After be added dimethyl sulphide, TLC tracking reaction stops reaction after without obvious raw material, and decompression is spin-dried for up to second compound；Its
In, the first compound, methylene chloride, methanol, dimethyl sulphide molal volume ratio be 2mmol:30ml:5ml:5ml.
Second compound is dissolved in benzene in S3, in addition by the synthetic method of the B- norcholesterol oxidized derivatives
Property aluminium oxide, TLC tracking reaction stops reaction after no raw material point, separates up to third compound；Wherein second compound, benzene,
The molal weight ratio of neutral alumina is 1.5mmol:18g:10mg.When separation, thick column was carried out to product with ethyl acetate, was subtracted
Pressure steams solvent, and crude product column chromatography for separation (mobile phase: ethyl acetate: petroleum ether=1:5) is to get third compound.
Third compound is dissolved in containing 2- methyl-in S4 by the synthetic method of the B- norcholesterol oxidized derivatives
It in the tetrahydrofuran of 2- butylene, is then added in the water containing sodium chlorite and sodium dihydrogen phosphate, is to be reacted at 30 DEG C in temperature,
TLC tracking reaction, after reaction, is removed under reduced pressure solvent, crude product column chromatography for separation to obtain the final productWherein, third compound, 2- methyl-2-butene, sodium chlorite, di(2-ethylhexyl)phosphate
Hydrogen sodium, tetrahydrofuran, water molal volume ratio be 0.1mmol:5mmol:1mmol:0.7mmol:1ml:1ml.The derivative
Property and nuclear magnetic data are as follows: m.p.118~121 DEG C1H NMR(CDCl3, 300MHz) and δ: 0.72 (3H, S, C18-H), 0.87
(3H,s,C26-C),0.89(3H,s,C27-C),0.9-0.95(6H,m,C21-H and CH3),0.99(3H,s, C19-H),
5.11(1H,m,OH).13C NMR(CDCl3, 75MHz) and δ: 178.23 (COOH), 173.21 (C=O)
Embodiment 4
S1, the first compound, the structural formula of the first compound are obtained after acylation reaction is occurred for cholesterol and RCOCl are as follows:R is
S2, the first compound is obtained to second compound, the structural formula of second compound after ozonization are as follows:
S3, by second compound and neutral alumina reactive aluminum, obtain third compound, third through intramolecular aldol condensation
Close the structural formula of object are as follows:
S4, by after third compound oxidation up to B- norcholesterol oxidized derivatives.
Cholesterol is dissolved in methylene chloride in S1, then by the synthetic method of the B- norcholesterol oxidized derivatives
Triethylamine, CH is added3COCl, is to react at 20 DEG C in temperature, and TLC tracking reaction stops reaction after raw material, separates up to the
One compound；Wherein, cholesterol, RCOCl, methylene chloride, triethylamine molal volume ratio be 1mmol:2mmol:20ml:
1ml.Wherein, separation, which is specifically included, carried out thick column with ethyl acetate, was evaporated under reduced pressure away extra ethyl acetate and dichloromethane
Alkane is dissolved with methylene chloride, is washed respectively with saturated sodium bicarbonate solution, saturated sodium chloride solution, is successively extracted three times, is merged
Organic phase, crude product column chromatography for separation (mobile phase: ethyl acetate: petroleum ether=1:10), obtaining target product is the first change
Close object.
First compound is dissolved in methylene chloride in S2 by the synthetic method of the B- norcholesterol oxidized derivatives,
Then methanol is added, is passed through O3, it is that 2h is reacted at -80 DEG C in temperature, TLC tracking is reacted, and stops being passed through O after no raw material point3, so
After be added dimethyl sulphide, TLC tracking reaction stops reaction after without obvious raw material, and decompression is spin-dried for up to second compound；Its
In, the first compound, methylene chloride, methanol, dimethyl sulphide molal volume ratio be 2mmol:30ml:5ml:5ml.
Second compound is dissolved in benzene in S3, in addition by the synthetic method of the B- norcholesterol oxidized derivatives
Property aluminium oxide, TLC tracking reaction stops reaction after no raw material point, separates up to third compound；Wherein second compound, benzene,
The molal weight ratio of neutral alumina is 1.5mmol:18g:10mg.When separation, thick column was carried out to product with ethyl acetate, was subtracted
Pressure steams solvent, and crude product column chromatography for separation (mobile phase: ethyl acetate: petroleum ether=1:5) is to get third compound.
Third compound is dissolved in containing 2- methyl-in S4 by the synthetic method of the B- norcholesterol oxidized derivatives
It in the tetrahydrofuran of 2- butylene, is then added in the water containing sodium chlorite and sodium dihydrogen phosphate, is to be reacted at 30 DEG C in temperature,
Solvent is removed under reduced pressure after reaction in TLC tracking reaction, and crude product column chromatography for separation is spread out up to up to the oxidation of B- norcholesterol
Biology；Wherein, the molal volume of third compound, 2- methyl-2-butene, sodium chlorite, sodium dihydrogen phosphate, tetrahydrofuran, water
Than for 0.1mmol:5mmol:1mmol:0.7mmol:1ml:1ml.The property and nuclear magnetic data of the derivative are as follows: m.p.150~
152℃.1H NMR(CDCl3, 300MHz) and δ: 0.72 (3H, S, C18-H), 0.87 (3H, d, C26-C), 0.90 (3H, d, C27-
C),0.93(3H,d,C21-C),1.02(3H,s,C19-H),5.32(1H,m,OH),7.11(2H,m, Ph-H),8.06(2H,
m,Ph-H).13C NMR(CDCl3, 75MHz) and δ: 177.94 (COOH), 165.07 (C=O)
Embodiment 5
S1, the first compound, the structural formula of the first compound are obtained after acylation reaction is occurred for cholesterol and RCOCl are as follows:R is
S2, the first compound is obtained to second compound, the structural formula of second compound after ozonization are as follows:
S3, by second compound and neutral alumina reactive aluminum, obtain third compound, third through intramolecular aldol condensation
Close the structural formula of object are as follows:
S4, by after third compound oxidation up to B- norcholesterol oxidized derivatives.
Cholesterol is dissolved in methylene chloride in S1, then by the synthetic method of the B- norcholesterol oxidized derivatives
Triethylamine, CH is added3COCl, is to react at 20 DEG C in temperature, and TLC tracking reaction stops reaction after raw material, separates up to the
One compound；Wherein, cholesterol, RCOCl, methylene chloride, triethylamine molal volume ratio be 1mmol:2mmol:20ml:
1ml.Wherein, separation, which is specifically included, carried out thick column with ethyl acetate, was evaporated under reduced pressure away extra ethyl acetate and dichloromethane
Alkane is dissolved with methylene chloride, is washed respectively with saturated sodium bicarbonate solution, saturated sodium chloride solution, is successively extracted three times, is merged
Organic phase, crude product column chromatography for separation (mobile phase: ethyl acetate: petroleum ether=1:10), obtaining target product is the first change
Close object.
First compound is dissolved in methylene chloride in S2 by the synthetic method of the B- norcholesterol oxidized derivatives,
Then methanol is added, is passed through O3, it is that 2h is reacted at -80 DEG C in temperature, TLC tracking is reacted, and stops being passed through O after no raw material point3, so
After be added dimethyl sulphide, TLC tracking reaction stops reaction after without obvious raw material, and decompression is spin-dried for up to second compound；Its
In, the first compound, methylene chloride, methanol, dimethyl sulphide molal volume ratio be 2mmol:30ml:5ml:5ml.
Second compound is dissolved in benzene in S3, in addition by the synthetic method of the B- norcholesterol oxidized derivatives
Property aluminium oxide, TLC tracking reaction stops reaction after no raw material point, separates up to third compound；Wherein second compound, benzene,
The molal weight ratio of neutral alumina is 1.5mmol:18g:10mg.When separation, thick column was carried out to product with ethyl acetate, was subtracted
Pressure steams solvent, and crude product column chromatography for separation (mobile phase: ethyl acetate: petroleum ether=1:5) is to get third compound.
Third compound is dissolved in containing 2- methyl-in S4 by the synthetic method of the B- norcholesterol oxidized derivatives
It in the tetrahydrofuran of 2- butylene, is then added in the water containing sodium chlorite and sodium dihydrogen phosphate, is to be reacted at 30 DEG C in temperature,
Solvent is removed under reduced pressure after reaction in TLC tracking reaction, and crude product column chromatography for separation is spread out up to up to the oxidation of B- norcholesterol
Biology；Wherein, the molal volume of third compound, 2- methyl-2-butene, sodium chlorite, sodium dihydrogen phosphate, tetrahydrofuran, water
Than for 0.1mmol:5mmol:1mmol:0.7mmol:1ml:1ml.The property and nuclear magnetic data of the derivative are as follows: m.p.110~
113℃.1H NMR(CDCl3, 300MHz) and δ: 0.72 (3H, S, C18-H), 0.87 (3H, s, C26-C), 0.90 (3H, s, C27-
C),0.94(3H,d,C21-C),1.02(3H,s,C19-H),7.42(2H,m,Ph-H),7.99(2H,m, Ph-H).13C NMR
(CDCl3, 75MHz) and δ: 177.63 (COOH), 165.18 (C=O)
Embodiment 6
S1, the first compound, the structural formula of the first compound are obtained after acylation reaction is occurred for cholesterol and RCOCl are as follows:R is
S2, the first compound is obtained to second compound, the structural formula of second compound after ozonization are as follows:
S3, by second compound and neutral alumina reactive aluminum, obtain third compound, third through intramolecular aldol condensation
Close the structural formula of object are as follows:
S4, by after third compound oxidation up to B- norcholesterol oxidized derivatives.
Cholesterol is dissolved in methylene chloride in S1, then by the synthetic method of the B- norcholesterol oxidized derivatives
Triethylamine, CH is added3COCl, is to react at 20 DEG C in temperature, and TLC tracking reaction stops reaction after raw material, separates up to the
One compound；Wherein, cholesterol, RCOCl, methylene chloride, triethylamine molal volume ratio be 1mmol:2mmol:20ml:
1ml.Wherein, separation, which is specifically included, carried out thick column with ethyl acetate, was evaporated under reduced pressure away extra ethyl acetate and dichloromethane
Alkane is dissolved with methylene chloride, is washed respectively with saturated sodium bicarbonate solution, saturated sodium chloride solution, is successively extracted three times, is merged
Organic phase, crude product column chromatography for separation (mobile phase: ethyl acetate: petroleum ether=1:10), obtaining target product is the first change
Close object.
First compound is dissolved in methylene chloride in S2 by the synthetic method of the B- norcholesterol oxidized derivatives,
Then methanol is added, is passed through O3, it is that 2h is reacted at -80 DEG C in temperature, TLC tracking is reacted, and stops being passed through O after no raw material point3, so
After be added dimethyl sulphide, TLC tracking reaction stops reaction after without obvious raw material, and decompression is spin-dried for up to second compound；Its
In, the first compound, methylene chloride, methanol, dimethyl sulphide molal volume ratio be 2mmol:30ml:5ml:5ml.
Second compound is dissolved in benzene in S3, in addition by the synthetic method of the B- norcholesterol oxidized derivatives
Property aluminium oxide, TLC tracking reaction stops reaction after no raw material point, separates up to third compound；Wherein second compound, benzene,
The molal weight ratio of neutral alumina is 1.5mmol:18g:10mg.When separation, thick column was carried out to product with ethyl acetate, was subtracted
Pressure steams solvent, and crude product column chromatography for separation (mobile phase: ethyl acetate: petroleum ether=1:5) is to get third compound.
Third compound is dissolved in containing 2- methyl-in S4 by the synthetic method of the B- norcholesterol oxidized derivatives
It in the tetrahydrofuran of 2- butylene, is then added in the water containing sodium chlorite and sodium dihydrogen phosphate, is to be reacted at 30 DEG C in temperature,
Solvent is removed under reduced pressure after reaction in TLC tracking reaction, and crude product column chromatography for separation is spread out up to up to the oxidation of B- norcholesterol
Biology；Wherein, the molal volume of third compound, 2- methyl-2-butene, sodium chlorite, sodium dihydrogen phosphate, tetrahydrofuran, water
Than for 0.1mmol:5mmol:1mmol:0.7mmol:1ml:1ml.The property and nuclear magnetic data of the derivative are as follows: m.p.175~
176℃.1H NMR(CDCl3, 300MHz) and δ: 0.71 (3H, S, C18-H), 0.86-0.88 (9H, m, C26-C, C27-H and
C21-H),0.92(3H,d,C19-C),3.64(2H,s,CH2),5.11(1H,m,OH),7.30-7.38(4H,m, Ph-H).13C
NMR(CDCl3, 75MHz) and δ: 181.20 (COOH), 170.56 (C=O)
Embodiment 7
S1, the first compound, the structural formula of the first compound are obtained after acylation reaction is occurred for cholesterol and RCOCl are as follows:R is
S2, the first compound is obtained to second compound, the structural formula of second compound after ozonization are as follows:
S3, by second compound and neutral alumina reactive aluminum, obtain third compound, third through intramolecular aldol condensation
Close the structural formula of object are as follows:
S4, by after third compound oxidation up to B- norcholesterol oxidized derivatives.
Cholesterol is dissolved in methylene chloride in S1, then by the synthetic method of the B- norcholesterol oxidized derivatives
Triethylamine, CH is added3COCl, is to react at 20 DEG C in temperature, and TLC tracking reaction stops reaction after raw material, separates up to the
One compound；Wherein, cholesterol, RCOCl, methylene chloride, triethylamine molal volume ratio be 1mmol:2mmol:20ml:
1ml.Wherein, separation, which is specifically included, carried out thick column with ethyl acetate, was evaporated under reduced pressure away extra ethyl acetate and dichloromethane
Alkane is dissolved with methylene chloride, is washed respectively with saturated sodium bicarbonate solution, saturated sodium chloride solution, is successively extracted three times, is merged
Organic phase, crude product column chromatography for separation (mobile phase: ethyl acetate: petroleum ether=1:10), obtaining target product is the first change
Close object.
First compound is dissolved in methylene chloride in S2 by the synthetic method of the B- norcholesterol oxidized derivatives,
Then methanol is added, is passed through O3, it is that 2h is reacted at -80 DEG C in temperature, TLC tracking is reacted, and stops being passed through O after no raw material point3, so
After be added dimethyl sulphide, TLC tracking reaction stops reaction after without obvious raw material, and decompression is spin-dried for up to second compound；Its
In, the first compound, methylene chloride, methanol, dimethyl sulphide molal volume ratio be 2mmol:30ml:5ml:5ml.
Second compound is dissolved in benzene in S3, in addition by the synthetic method of the B- norcholesterol oxidized derivatives
Property aluminium oxide, TLC tracking reaction stops reaction after no raw material point, separates up to third compound；Wherein second compound, benzene,
The molal weight ratio of neutral alumina is 1.5mmol:18g:10mg.When separation, thick column was carried out to product with ethyl acetate, was subtracted
Pressure steams solvent, and crude product column chromatography for separation (mobile phase: ethyl acetate: petroleum ether=1:5) is to get third compound.
Third compound is dissolved in containing 2- methyl-in S4 by the synthetic method of the B- norcholesterol oxidized derivatives
It in the tetrahydrofuran of 2- butylene, is then added in the water containing sodium chlorite and sodium dihydrogen phosphate, is to be reacted at 30 DEG C in temperature,
TLC tracking reaction, after reaction, is removed under reduced pressure solvent, crude product column chromatography for separation is up to B- norcholesterol oxidization deriving
Object；
Wherein, mole body of third compound, 2- methyl-2-butene, sodium chlorite, sodium dihydrogen phosphate, tetrahydrofuran, water
Product is than being 0.1mmol:5mmol:1mmol:0.7mmol:1ml:1ml.The property and nuclear magnetic data of the derivative are as follows: m.p.113
~114 DEG C of1H NMR(CDCl3, 300MHz) δ: 0.70 (3H, S, C18-H), 0.85 (3H, s, C26-H), 0.87 (3H, s,
C27-H),0.92(3H,d,C21-H),1.00(3H,s,C19-H),5.31(1H,m,OH),6.48(1H,m, CH),7.20
(1H,d,CH),7.55(2H,s,CH).13C NMR(CDCl3, 75MHz) and δ, 177.88 (COOH), 157.91 (C=O),
146.35 (C=C), 144.69 (C=C), 118.15 (C=C), 111.87 (C=C)
In order to assess the extracorporeal suppression tumor cell growing multiplication activity of synthesized compound, we are with people's breast ductal cancer
Cell (T47D), Proliferation of Human Ovarian Cell (SKOV3), human breast cancer cell (MCF-7) are made as research object using mtt assay
The compound synthesized by embodiment 2~7 carries out the test of anti tumor activity in vitro to three of the above cancer cell, tests IC50, test
The results are shown in Table 1.
Table 1- difference Compound ira vitro inhibitory activity (mtt assay) (IC50,μmol/L)
As seen from the above table, the compound that embodiment 2~7 is prepared to human breast cancer cell, human milk gland ductal carcinoma cells,
Proliferation of Human Ovarian Cell has significant inhibition growth of tumour cell cultivation effect, can be used as pharmaceutical intermediate or medicinal application in not
Same drug manufacture and purposes.
Although the embodiments of the present invention have been disclosed as above, but its is not only in the description and the implementation listed
With it can be fully applied to various fields suitable for the present invention, for those skilled in the art, can be easily
Realize other modification, therefore without departing from the general concept defined in the claims and the equivalent scope, the present invention is simultaneously unlimited
In specific details.
Claims (7)
1.B- norcholesterol oxidized derivatives, which is characterized in that the structural formula of the compound are as follows:
Wherein, R CH3、CH3CH2CH2、CH3CH2CH2CH2、One of.
2. the synthetic method of B- norcholesterol oxidized derivatives as described in claim 1, which is characterized in that including following step
It is rapid:
S1, the first compound, the structural formula of the first compound are obtained after acylation reaction is occurred for cholesterol and RCOCl are as follows:
S2, the first compound is obtained to second compound, the structural formula of second compound after ozonization are as follows:
S3, by second compound and neutral alumina reactive aluminum, obtain third compound, third compound through intramolecular aldol condensation
Structural formula are as follows:
S4, by after third compound oxidation up to B- norcholesterol oxidized derivatives.
3. the synthetic method of B- norcholesterol oxidized derivatives as claimed in claim 2, which is characterized in that by cholesterol in S1
It is dissolved in methylene chloride, triethylamine, RCOCl is then added, after temperature is to react at 20~25 DEG C, separate up to the first chemical combination
Object；Wherein, cholesterol, RCOCl, methylene chloride, triethylamine molal volume ratio be 0.9~1.1mmol:1.9~2.1mmol:
18~22ml:0.8~1.2ml.
4. the synthetic method of B- norcholesterol oxidized derivatives as claimed in claim 2, which is characterized in that change in S2 by first
It closes object to be dissolved in methylene chloride, methanol is then added, is passed through O3, it is to react 2~4h at -80~-60 DEG C in temperature, is then added
Dimethyl sulphide, the reaction was continued 4~6h, decompression are spin-dried for up to second compound；Wherein, the first compound, methylene chloride, methanol,
The molal volume ratio of dimethyl sulphide is 1.9~2.1mmol:28~32ml:4~6ml:4~6ml.
5. the synthetic method of B- norcholesterol oxidized derivatives as claimed in claim 2, which is characterized in that change in S3 by second
It closes object to be dissolved in benzene, neutral alumina is added, after the reaction was completed, separate up to third compound；Wherein second compound, benzene,
The molal weight ratio of neutral alumina is 1.4~1.6mmol:18~20g:9~11mg.
6. the synthetic method of B- norcholesterol oxidized derivatives as claimed in claim 2, which is characterized in that by third in S4
It closes object to be dissolved in the tetrahydrofuran containing 2- methyl-2-butene, then be added in the water containing sodium chlorite and sodium dihydrogen phosphate, in
Temperature is to react at 30~40 DEG C, is separated up to B- norcholesterol oxidized derivatives；Wherein, third compound, 2- methyl -2- fourth
Alkene, sodium chlorite, sodium dihydrogen phosphate, tetrahydrofuran, water molal volume ratio be 0.09~0.11mmol:4.8~5.2mmol:
0.8~1.1mmol:0.6~0.8mmol:1~1.2ml:0.9~1.1ml.
7. B- norcholesterol oxidized derivatives application in preparation of anti-tumor drugs as described in claim 1.
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