CN107236013A - The alkane ester group pregnane compound of 20 hydroxyl pregnene 3 and its synthetic method and the application in antineoplastic is prepared - Google Patents
The alkane ester group pregnane compound of 20 hydroxyl pregnene 3 and its synthetic method and the application in antineoplastic is prepared Download PDFInfo
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- CN107236013A CN107236013A CN201710619741.1A CN201710619741A CN107236013A CN 107236013 A CN107236013 A CN 107236013A CN 201710619741 A CN201710619741 A CN 201710619741A CN 107236013 A CN107236013 A CN 107236013A
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- 0 CCOC(C)C(CC1)C(C)(CC2)C1C1C2C(C)(CCC(*)C2)C2=CC1 Chemical compound CCOC(C)C(CC1)C(C)(CC2)C1C1C2C(C)(CCC(*)C2)C2=CC1 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
- C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
- C07J7/0065—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by an OH group free esterified or etherified
- C07J7/007—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by an OH group free esterified or etherified not substituted in position 17 alfa
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Abstract
The invention discloses a kind of alkane ester group pregnane compound of 20 hydroxyl pregnene 3, the steroid nucleus structural formula of the compound is as follows：Wherein, R groups can be：R=CCl3, CH2CH3.The invention also discloses the synthetic method of the alkane ester group pregnane compound of 20 hydroxyl pregnene 3, comprise the following steps：Using steroidal compounds pregnenolone as raw material, first by 3 hydroxyls of pregnenolone by alkyl esterification of acyl chloride into ester, reaction obtains intermediate product, then by 17 carbonyl reductions of intermediate product, that is, obtains the alkane ester group pregnane compound of 20 hydroxyl pregnene 3.The alkane ester group pregnane compound of 20 hydroxyl pregnene 3 of the present invention is inhibited to the growing multiplication of some cancer cells, can be manufactured and purposes in different antineoplastics as pharmaceutical intermediate or medicinal application.
Description
Technical field
The present invention relates to compound synthesis technical field, it is more particularly related to 20- hydroxyls-pregnene -3- alkane
Ester group pregnane compound and its synthetic method and the application in antineoplastic is prepared.
Background technology
Pregnenolone has weaker anti-inflammatory activity in itself, and document once reported C3- hydroxy esterifications of pregnenolone, salicylic acid
Ester and formic acid esters have an antiinflammatory action suitable with the cortisone of clinical practice, and trichloroacetic esters, chloracetate, furans -2 '-acid
Ester, p-methyl benzenesulfonic acid ester, phthalic acid ester have compared with antiflamison slightly strong antiinflammatory action (pregnant steroids of the .5- such as Li Zhensu, Wang Haiqing
The synthesis of alkene -3 β, 17 α--17 α of bis- alcohol -20- ketone -3- acetates-fatty acid ester and its structure activity study [J] pharmacy
Report, 1983,18 (2):119-124.).
Seminar has been chemically modified the correlative study of transformation to pregnenolone, " pregnenolone aromatic aldehyde azine steroid
Body compound and its synthetic method and the application in antineoplastic is prepared " (Chinese invention patent, application number：
201310184358.X, application publication number CN103254264A), " 3- substitutions-B-Homo- steroidals-B- cyclic lactams compound and
Its preparation method and the application in antineoplastic is prepared " (Chinese invention patent, application number：201110009124.2, application
Publication No.：CN102146115A), " have ammonia derivative branched structure 3- hydroxyls -5- en steroids compounds process for production thereof and its
Application in antineoplastic " (Chinese invention patent, application number：201210330275.2, application publication number：
CN102816198A)。
But, relevant 20- hydroxyls-pregnene -3- alkane ester group pregnane compounds and its synthetic method and its prepare it is anti-
Application in tumour medicine has no report.
The content of the invention
It is an object of the invention to provide a kind of 20- hydroxyls-pregnene -3- alkane ester group pregnane compounds.
It is a further object of the present invention to provide the synthetic method of above-claimed cpd.
The further object of the present invention is to provide application of the above-claimed cpd in antineoplastic is prepared.
The present invention is achieved through the following technical solutions above-mentioned purpose, and 20- hydroxyls-pregnene -3- alkane ester groups of the invention are pregnant
The steroid nucleus structural formula of steroid compound is as follows：
Wherein, R- groups can be：R=-CCl3、-CH2CH3。
Preferably, comprise the following steps：Using steroidal compounds pregnenolone as raw material, first by the 3- positions of pregnenolone
Hydroxyl is by alkyl esterification of acyl chloride into ester, and reaction obtains intermediate product, then by the 17- positions carbonyl reduction of intermediate product, produces
To 20- hydroxyls-pregnene -3- alkane ester group pregnane compounds.
Preferably, 3- hydroxyls are by the reaction method of alkyl esterification of acyl chloride into ester：Pregnenolone is dissolved in pyrrole
Pyridine, is stirred at a temperature of 40 DEG C, is slow added into alkyl acyl chlorides, and TLC tracking reactions, to without reaction is stopped after raw material point, are obtained
To reaction product first add frozen water, then be extracted with ethyl acetate, merge organic phase, successively with 1mol/L watery hydrochloric acid, saturation
NaHCO3, distilled water, saturation NaCl washing washings, then use anhydrous Na2SO4Dry, organic solvent, post layer are fallen in last vacuum distillation
Analysis separation, obtains white needle-like crystals, as intermediate product；
Wherein, the alkyl acyl chlorides is trichloro-acetic chloride or propionyl chloride.
Preferably, the reaction method of 17- carbonyl reductions is：By the intermediate product and CH2Cl2Mixing, in 40 DEG C of temperature
Lower stirring to the intermediate product of degree is completely dissolved, and adds CeCl3·7H2O and CH3OH, treats CeCl3·7H2After O is completely dissolved,
Weigh NaBH4It is slowly added to be reacted, reacts at room temperature, TLC detections, reaction adds 1mol/ to stopping reacting without raw material point
Reaction is quenched in L watery hydrochloric acid, and vacuum distillation is fallen after organic solvent, adds distilled water, is extracted with ethyl acetate, and merges organic phase, then
Washed successively with water, saturation NaCl solution, then use anhydrous Na2SO4Dry, organic solvent, column chromatography point are fallen in last vacuum distillation
From obtaining the end-product of white solid, as described 20- hydroxyls-pregnene -3- alkane ester group pregnane compounds.
Described 20- hydroxyls-application of the pregnene -3- alkane ester group pregnane compounds in antineoplastic is prepared.
Described 20- hydroxyls-pregnene -3- alkane ester groups pregnane compound is anti-in preparation for the Pharmaceutical composition of active component
Application in tumour medicine.
The reaction scheme for preparing the 20- hydroxyls-pregnene -3- alkane ester group pregnane compounds is as follows：
Wherein, the R group in compound 1 to 4 is as follows：1R=-CCl3, 2R=-CH2CH3, 3R=-CCl3、4、R
=-CH2CH3；Reagent and condition：A, pyridine, CCl3COCl、CH3CH2COCl；b:CH3OH、CH2Cl2、CeCl3·7H2O、NaBH4。
Shown by physiologically active experimental study, 20- hydroxyls-pregnene -3- ester groups pregnane compound 3 of the invention and 4 pairs
It is inhibited to the growing multiplication of human lung adenocarcinoma cell line, can be antitumor in difference as pharmaceutical intermediate or medicinal application
Medicine is manufactured and purposes.
Further advantage, target and the feature of the present invention embodies part by following explanation, and part will also be by this
The research and practice of invention and be understood by the person skilled in the art.
Embodiment
With reference to embodiment, the present invention is described in further detail, to make those skilled in the art with reference to specification
Word can be implemented according to this.
It should be noted that experimental method described in following embodiments, is conventional method unless otherwise specified, institute
Reagent and material are stated, unless otherwise specified, is commercially obtained.
<Embodiment 1>The preparation of 20- acetylsalicylic acid pregnene ester -3- trichloroacetic esters (3)
Step 1:The preparation of pregnene -3- trichloroacetic esters (1)
0.320g (1.01mmol) pregnenolones are weighed in 100mL eggplant type flasks, 15ml pyridines are added under fume hood, are put
Stirred in 40 DEG C of oil bath pans, after dissolution of raw material is complete, pipettes 400uL (3.58mmol) trichloro-acetic chloride and be slowly added to reaction,
TLC tracking reactions stop reaction to after almost being disappeared without raw material point, react 12h, first add 15ml ice distilled water to reaction bulb, use
Ethyl acetate extracts 4 times (15mL × 4), combining extraction liquid, successively with 1mol/L watery hydrochloric acid, saturation NaHCO3, distilled water, saturation
NaCl is washed, then uses anhydrous Na2SO4Dry, then vacuum distillation, column chromatography for separation (eluant, eluent：V petroleum ethers:V ethyl acetate=
5:1) white needle-like crystals 0.396g, m.p.174-177 DEG C, yield are obtained：85.0%, product structure is analyzed through IR, NMR and MS
It is determined that；
Step 2:The preparation of 20- hydroxyls-pregnene -3- trichloroacetic esters (3)
0.289g (0.63mmol) compound (1) is weighed in 100mL eggplant type flasks, 10mL CH are added2Cl2, it is placed in 40
DEG C stirred in water bath, after solid dissolving is complete, adds 0.242g (0.65mmol) CeCl3·7H20、5mL CH3OH, is completely dissolved
Afterwards, continue to stir 15min, 0.118g (3.12mmol) NaBH is finally added portionwise4, continue to stir 5min, TLC tracking after adding
Reaction is to without stopping reaction after raw material point.Reaction is quenched with 1mol/L watery hydrochloric acid, most of solvent is spun off, 15mL distillations are added
Water, is extracted with ethyl acetate 4 times (15mL × 4), organic phase washed with water, saturation NaCl washings, anhydrous Na2SO4 is dried, decompression
Distillation, column chromatography for separation (eluant, eluent：V petroleum ethers:V ethyl acetate=6:1) white powdery solids 0.261g is obtained,
M.p.177-179 DEG C, yield：90.0%, through IR, NMR and MS analysis determine product structure be 20- acetylsalicylic acid pregnene ester-
3- trichloroacetic esters.
<Embodiment 2>The preparation of (4) of 20- acetylsalicylic acid pregnene ester -3- propionic esters
Step 1:The preparation of pregnene -3- propionic esters (2)
0.322g (1.02mmol) pregnenolones are weighed in 100mL eggplant type flasks, 15ml pyridines are added under fume hood, are put
In 40 DEG C of oil bath pans stir, after dissolution of raw material is complete, pipette 400uL (4.59mmol) propionyl chloride be slowly added to reaction, TLC with
Track, which is reacted to after almost being disappeared without raw material point, stops reaction, reacts 12h, first adds 15ml ice distilled water to reaction bulb, use acetic acid
Ethyl ester extracts 4 times (15mL × 4), combining extraction liquid, successively with 1mol/L watery hydrochloric acid, saturation NaHCO3, distilled water, saturation NaCl
Washing, then use anhydrous Na2SO4Dry, then vacuum distillation, column chromatography for separation (eluant, eluent：V petroleum ethers:V ethyl acetate=5:1)
Obtain white needle-like crystals 0.368g, m.p.124-126 DEG C, yield：97.1%, product structure analyzes true through IR, NMR and MS
It is fixed；
Step 2:The preparation of 20- hydroxyls-pregnene -3- propionic esters (4)
0.290g (0.78mmol) compound (2) is weighed in 100mL eggplant type flasks, 10mL CH are added2Cl2, it is placed in 40
DEG C stirred in water bath, after solid dissolving is complete, adds 0.302g (0.81mmol) CeCl37H20、5mL CH3OH, is completely dissolved
Afterwards, continue to stir 15min, 0.141g (3.71mmol) NaBH is finally added portionwise4, continue to stir 5min, TLC tracking after adding
Reaction is quenched with 1mol/L watery hydrochloric acid to without reaction is stopped after raw material point in reaction, spins off most of solvent, adds 15mL distillations
Water, is extracted with ethyl acetate 4 times (15mL × 4), organic phase washed with water, saturation NaCl washings, anhydrous Na2SO4Dry, decompression
Distillation, column chromatography for separation (eluant, eluent：V petroleum ethers:V ethyl acetate=6:1) white powdery solids 0.274g is obtained,
M.p.153-155 DEG C, yield：90.0%.Through IR, NMR and MS analysis determine product structure be 20- acetylsalicylic acid pregnene ester-
3- propionic esters.
Some tumour cells are carried out using 20- hydroxyls of the present invention-pregnene -3- alkane ester group pregnane compounds thin
Cellular toxicity is tested, it is found that some of which compound has significant suppression growth of tumour cell cultivation effect.Such as compound 3 in table
With the inhibitory action of 4 pairs of human lung adenocarcinoma cell lines (A549).
The IC of the compound 3 of table 1,4 pairs of human lung adenocarcinoma cell lines50It is worth (μm ol/L)
| Compound | 3 | 4 |
| IC50 | 7.9 | 10.3 |
Although embodiment of the present invention is disclosed as above, it is not restricted in specification and embodiment listed
With it can be applied to various suitable the field of the invention completely, can be easily for those skilled in the art
Other modification is realized, therefore under the universal limited without departing substantially from claim and equivalency range, the present invention is not limited
In specific details.
Claims (6)
1. a kind of 20- hydroxyls-pregnene -3- alkane ester group pregnane compounds, it is characterised in that the steroid nucleus structural formula of the compound is such as
Shown in lower：
Wherein, R- groups can be：R=-CCl3、-CH2CH3。
2. the synthetic method of 20- hydroxyls as claimed in claim 1-pregnene-3- alkane ester group pregnane compounds, its feature exists
In comprising the following steps：Using steroidal compounds pregnenolone as raw material, the 3- positions hydroxyl of pregnenolone is passed through into alkyl first
Esterification of acyl chloride is into ester, and reaction obtains intermediate product, then by the 17- positions carbonyl reduction of intermediate product, that is, obtains 20- hydroxyl-pregnene-
3- alkane ester group pregnane compounds.
3. the synthetic method of 20- hydroxyls as claimed in claim 2-pregnene-3- alkane ester group pregnane compounds, its feature exists
In 3- hydroxyls are by the reaction method of esterification of acyl chloride into ester：
Pregnenolone is dissolved in pyridine, stirred at a temperature of 40 DEG C, alkyl acyl chlorides, TLC tracking reactions, to nothing is slow added into
Stop reaction after raw material point, obtained reaction product first adds frozen water, then is extracted with ethyl acetate, merge organic phase, use successively
1mol/L watery hydrochloric acid, saturation NaHCO3, distilled water, saturation NaCl washing washings, then use anhydrous Na2SO4Dry, finally decompression is steamed
Evaporate organic solvent, column chromatography for separation obtains white needle-like crystals, as intermediate product；
Wherein, the alkyl acyl chlorides is trichloro-acetic chloride or propionyl chloride.
4. the synthetic method of 20- hydroxyls as claimed in claim 3-pregnene-3- alkane ester group pregnane compounds, its feature exists
In the reaction method of 17- carbonyl reductions is：
By the intermediate product and CH2Cl2Mixing, stirs to the intermediate product at a temperature of 40 DEG C and is completely dissolved, and adds
CeCl3·7H2O and CH3OH, treats CeCl3·7H2After O is completely dissolved, NaBH is weighed4It is slowly added to be reacted, at room temperature instead
Should, TLC detections, reaction adds 1mol/L watery hydrochloric acid and reaction is quenched, organic solvent is fallen in vacuum distillation to stopping reacting without raw material point
Afterwards, distilled water is added, is extracted with ethyl acetate, merges organic phase, then is washed successively with water, saturation NaCl solution, then with nothing
Water Na2SO4Dry, organic solvent is fallen in last vacuum distillation, and column chromatography for separation obtains the end-product of white solid, be described
20- hydroxyls-pregnene -3- alkane ester group pregnane compounds.
5. 20- hydroxyls-pregnene -3- alkane ester group pregnane compounds as claimed in claim 1 are in antineoplastic is prepared
Using.
6. 20- hydroxyls as claimed in claim 1-pregnene-3- alkane ester groups pregnane compound is the pharmaceutical compositions of active component
Application of the thing in antineoplastic is prepared.
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| CN201710619741.1A CN107236013A (en) | 2017-07-26 | 2017-07-26 | The alkane ester group pregnane compound of 20 hydroxyl pregnene 3 and its synthetic method and the application in antineoplastic is prepared |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4189400A (en) * | 1977-08-17 | 1980-02-19 | Bonderman Dean P | Compound useful in cholesterol assay procedures |
| WO1997015558A1 (en) * | 1995-10-23 | 1997-05-01 | Merck & Co., Inc. | 17-alkyl-7-substituted-4-aza steroid derivatives |
| WO2011138460A1 (en) * | 2010-05-07 | 2011-11-10 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Progesterone receptor antagonists and uses thereof |
-
2017
- 2017-07-26 CN CN201710619741.1A patent/CN107236013A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4189400A (en) * | 1977-08-17 | 1980-02-19 | Bonderman Dean P | Compound useful in cholesterol assay procedures |
| WO1997015558A1 (en) * | 1995-10-23 | 1997-05-01 | Merck & Co., Inc. | 17-alkyl-7-substituted-4-aza steroid derivatives |
| WO2011138460A1 (en) * | 2010-05-07 | 2011-11-10 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Progesterone receptor antagonists and uses thereof |
Non-Patent Citations (1)
| Title |
|---|
| MAUVAIS等: "Inhibition of ecdysone biosynthesis:preparation of acetylenic intermediates", 《TETRAHEDRON》 * |
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