CN108530510A - A kind of C19- is acylated the preparation method of triptolide - Google Patents
A kind of C19- is acylated the preparation method of triptolide Download PDFInfo
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- CN108530510A CN108530510A CN201710121312.1A CN201710121312A CN108530510A CN 108530510 A CN108530510 A CN 108530510A CN 201710121312 A CN201710121312 A CN 201710121312A CN 108530510 A CN108530510 A CN 108530510A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
- C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
- C07J73/003—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by oxygen as hetero atom
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The present invention provides the preparation methods that a kind of C19 is acylated triptolide, and specifically, the method for the present invention is prepared C19 by carrying out monoacylation to compound of formula I, by three-step reaction and is acylated triptolide.The present invention overcomes the bad disadvantage of regioselectivity in existing method, high income, raw material availability is high.
Description
Technical field
The invention belongs to organic chemistry, pharmaceutical chemistry and field of natural medicinal chemistry, specifically relate to a kind of C19- acylations thunder
The preparation method of public rattan A prime.
Background technology
Tripterygium wilfordii (Triptergium wilfordii Hook.f) is the annual liana of Celastraceae, is China's tradition
A kind of common Chinese herbal medicine in medicine.Its is warm-natured, bitter and puckery flavor, has anti-inflammatory, antirheumatic, analgesic isoreactivity.Triptolide is again
Claim triptolide, is one of main active of tripterygium wilfordii.It mainly extracts from the leaf of tripterygium wilfordii and root and obtains, tool
There are the multiple biological activities such as immunosupress, anti-inflammatory, antifertility, antitumor, desinsection, is clinically used for treatment psoriasis, rheumatoid
Arthritis, leukaemia, nephrosis etc., but its toxicity is the main reason for restricting such compound clinical application.C19- benzoylations
Triptolide refers to 19 derivatives obtained after introducing benzoyl in tripterygium wilfordii, shows apparent antitumor work
Property, while the toxicity of the compound has apparent attenuating compared with triptolide, has good clinical development foreground.
The existing synthetic method about C19- benzoylation triptolides only has one kind, CN 1925852A and WO
It is had been described in 2005/084365 A2.Specific synthetic route is as follows：
Dibenzoyl is obtained by the reaction using the triptolide of C14 hydroxyl protections as raw material, with chlorobenzoyl chloride in the route
Derivative, then removing first sulfidomethyl obtains dibenzoyl triptolide under mercury chloride effect, finally again in acid item
Hydrolysis obtains single benzoyl compound under part.This synthetic route takes the strategy that first bisacylation hydrolyzes again, causes in this way
The waste of raw material；Meanwhile acylating reagent is adopted benzoyl chloride as in one step of double acylations, reagent needs are significantly excessive, and
It seriously causes yield relatively low with LDA side reactions.So this route cost is higher, poor operability is not suitable for industrial metaplasia
Production.
In conclusion there is an urgent need in the art to a kind of methods for preparing C19- and being acylated triptolide.
Invention content
The object of the present invention is to provide a kind of methods for preparing C19- and being acylated triptolide.
The first aspect of the present invention provides a kind of preparation method of C19- acylation triptolides (IV), the side
Method includes step：
(a) in atent solvent, under alkaline condition, with formula (I) compound and aldehyde compound R2- CHO reacts, and obtains
Formula (II) compound：
(b) in atent solvent, oxidation reaction is carried out with formula (II) compound, to obtain formula (III) compound：
(c) in atent solvent, formula (III) compound deprotection group obtains formula (IV) compound：
Wherein R1For first sulfidomethyl, acetyl group, trimethylsilyl, R2For phenyl, C1-C10 alkyl, contains C3-C8 naphthenic base
The 1-4 heteroatomic 5-10 circle heterocyclic rings bases for being selected from N, O or S.
In another preferred example, the step (c) is in HgCl2In the presence of carry out.
In another preferred example, in the step (c), the atent solvent is selected from the group：Acetonitrile, water or its group
It closes.
In another preferred example, R1For first sulfidomethyl, R2For phenyl.
In another preferred example, in the step a), the reaction carries out in the presence of alkali selected from the group below：Two is different
Propyl amido lithium (LDA), n-BuLi (n-BuLi), tert-butyl lithium (t-BuLi), hexamethyldisilazide lithium (LiHMDS),
Two silicon substrate amido (NaHMDS) of hexamethyl, sodium hydride (NaH).
In another preferred example, in the step (a), the ratio of the alkali and formula (I) compound is (0.8-
4.0):1, preferably (1.0-2.0):1.
In another preferred example, described with aldehyde compound R in the step (a)2- CHO and formula (I) compound
Ratio be (0.8-3.0):1, preferably (1.0-2.0):1.
In another preferred example, in the step (b), the ratio of the compound ii and oxidant is (0.8-
3.0):1, preferably (1.0-2.0):1.
In another preferred example, in the step (a), the atent solvent is selected from the group tetrahydrofuran and ether,
It is preferred that tetrahydrofuran.
In another preferred example, in the step (a), the reaction temperature be -78~25 DEG C, preferably -78~0
℃。
In another preferred example, in the step (a), the reaction time be 30 minutes~24 hours, preferably 60
Minute~12 hours.
In another preferred example, the method for oxidation used in the oxidation reaction described in step (b) is selected from the group：Dess-
Martin is aoxidized, IBX oxidations, Swern oxidations, Moffatt oxidations, MnO2Oxidation, SeO2Oxidation, Collins oxidations, Jones oxygen
Change, PCC oxidations, PDC oxidations.
In another preferred example, in the step (b), oxidising agent is selected from down used in the oxidation reaction
Group：Dess-Martin oxidants, IBX oxidants, Swern oxidants, Moffatt oxidants, MnO2Oxidant, SeO2Oxidation
Agent, Collins oxidants, Jones oxidants, PCC oxidants, PDC oxidants.
In another preferred example, in the step (b), the atent solvent is selected from the group：Ethyl acetate, dichloromethane
Alkane, chloroform, tetrahydrofuran, ether, acetonitrile, Isosorbide-5-Nitrae-dioxane, n,N-Dimethylformamide, n,N-dimethylacetamide, two
First sulfoxide, or combinations thereof.
In another preferred example, in the step (b), the reaction temperature is 0~25 DEG C.
In another preferred example, in the step (b), the reaction time be 30 minutes~24 hours, preferably 60
Minute~12 hours.
In another preferred example, the R2It is selected from the group：Phenyl, 2- furyls, 3- furyls, 2- thienyls, 3- thiophenes
Pheno base, 2- pyridyl groups, 3- pyridyl groups, 4- pyridyl groups, C1-C10 alkyl.
The second aspect of the present invention provides a kind of preparation method of C19- acylation triptolides (IV), feature
It is, the method includes the steps：
C) in atent solvent, formula (III) compound deprotection group obtains formula (IV) compound：
Wherein, the definition of each group is as described in first aspect present invention.
In another preferred example, the method further includes step：
B) in atent solvent, oxidation reaction is carried out with formula (II) compound, to obtain formula (III) compound.
It is intermediate to provide a kind of C19- acylation triptolide preparations being shown below for the third aspect of the present invention
Body：
Wherein, X is selected from the group：-OH、O；
Wherein R1It is selected from the group：First sulfidomethyl, acetyl group, trimethylsilyl, R2For phenyl, C1-C10 alkyl, C3-C8 cycloalkanes
Base, the heteroatomic 5-10 unit's heteroaryls for being selected from N, O or S containing 1-4；
Dotted line indicates chemical bond or nothing.
It should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the invention and have in below (eg embodiment)
It can be combined with each other between each technical characteristic of body description, to form a new or preferred technical solution.As space is limited, exist
This no longer tires out one by one states.
Specific implementation mode
The present inventor in-depth study by long-term, it has unexpectedly been found that a kind of C19- is acylated the system of triptolide
Preparation Method, the preparation method use compound of formula I as raw material, it is possible to prevente effectively from incidental double in the prior art
Site acylation reaction, raw material availability are high.And the method can be used for a series of preparation of related activity compounds.
Term
As used herein, " C1-C6 alkyl " refers to the alkyl for the linear chain or branched chain for including 1-6 carbon atom, such as methyl,
Ethyl, propyl, isopropyl, butyl, isobutyl group, tertiary butyl or similar group.
As used herein, " C3-C8 naphthenic base " refers to including the naphthenic base of 3-8 carbon atom, such as cyclopropyl, ring fourth
Base, cyclopenta, cyclohexyl or similar group.
As used herein, " 5-10 circle heterocyclic rings base " refers to the ring group for including 5-10 annular atom, and the ring group can be
It is all unsaturated, part insatiable hunger and/or with armaticity, such as cyclopropyl, cyclobutyl, pyrrole radicals, morpholinyl or similar base
Group.
C19- is acylated the synthesis of triptolide
The purpose of the present invention is overcoming the deficiencies in the prior art, a kind of novel formula (IV) C19- acylations thunder is provided
The synthetic method of public rattan A prime.
The present invention provides the preparation methods that a kind of C19- is acylated triptolide (IV), include the following steps：
A) formula (II) compound is reacted with aldehyde compound by formula (I) compound under alkaline condition, reaction equation is such as
Under：
B) formula (III) compound is reacted under oxidant effect by formula (II) compound, reaction equation is as follows：
C) formula (III) compound deprotection group obtains formula (IV) compound, and reaction equation is as follows：
Wherein R1 is first sulfidomethyl, acetyl group, trimethylsilyl, R2For phenyl, C1-C10 alkyl, contains C3-C8 naphthenic base
The 1-4 heteroatomic 5-10 unit's heteroaryls for being selected from N, O or S.R1For first sulfidomethyl, acetyl group, trimethylsilyl, R2For phenyl,
C1-C10 alkyl, C3-C8 naphthenic base, the heteroatomic 5-10 circle heterocyclic rings base for being selected from N, O or S containing 1-4, preferably R1 are first sulphur
Methyl, R2For phenyl.
The alkali used in condensation reaction described in step (a) is selected from lithium diisopropyl amido (LDA), n-BuLi (n-
BuLi), tert-butyl lithium (t-BuLi), hexamethyldisilazide lithium (LiHMDS), sodium hexamethyldisilazide (NaHMDS),
Sodium hydride (NaH), preferably lithium diisopropyl amido (LDA)；The ratio of alkali and formula (I) compound is (0.8-4.0):1, preferably
(1.0-2.0):1。
Condensation reaction described in step (a) carries out in a solvent, solvent used be tetrahydrofuran and ether, preferably four
Hydrogen furans；- 78~25 DEG C of temperature used, preferably -78~0 DEG C；Reaction time be 0.5 hour~24 hours, preferably 1 hour~12
Hour.
The method for oxidation used in oxidation reaction described in step (b) aoxidizes for Dess-Martin, IBX oxidations, Swern
Oxidation, Moffatt oxidations, MnO2Oxidation, SeO2Oxidation, Collins oxidations, Jones oxidations, PCC oxidations, PDC oxidations, preferably
Dess-Martin is aoxidized, MnO2Oxidation, Swern oxidations.
The oxidation reaction used in oxidation reaction described in step (b) carries out in a solvent, and solvent for use is ethyl acetate,
Dichloromethane, chloroform, tetrahydrofuran, ether, acetonitrile, Isosorbide-5-Nitrae-dioxane, n,N-Dimethylformamide, N, N- dimethylacetamides
One or more of amine, dimethyl sulfoxide, ethyl acetate, dichloromethane.
In a preferred experimental program of the invention, the complete synthetic route of C19- benzoyl triptolides is such as
Shown in lower：
In the present invention, the intermediate being prepared such as formula (II) and formula (III) compound can be further used for preparing
Other C-19 benzoyl triptolide intermediates or prodrug.For example, can be used for preparing formula (V) compound：
D) in atent solvent, with formula (II) compound deprotection group, formula (V) compound is obtained：
The advantages of present invention is relative to existing synthetic route：
1) regioselectivity of the reaction is more preferable, avoids C18 and C19 while being acylated；
2) the reaction yield higher, the very big utilization rate for improving raw material；
3) application range of the reaction is wider, and target acylate but also the corresponding alcohols of synthesis can be obtained by the method
Intermediate and related derivative product.
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention
Rather than limit the scope of the invention, it is reference with this technology, it is modified or improved and belongs to protection scope of the present invention
It is interior.In the following examples, the experimental methods for specific conditions are not specified, usually according to normal condition, or according to proposed by manufacturer
Condition.Unless otherwise stated, otherwise percentage and number are calculated by weight.
The synthesis of 1 C19- benzoyl triptolides of embodiment
Step 1)
Under argon gas protection, compound 1 (1.26g, 3.0mmol) is dissolved in dry tetrahydrofuran (30mL), has been stirred
- 78 DEG C are gradually cooled to after fully dissolved, be slowly added dropwise at this temperature heptane/ethylbenzene/tetrahydrofuran LDA solution (2.4mL,
3.6mmol).Drop finishes, and benzaldehyde (0.48mL, 4.5mmol) is slowly added dropwise after this temperature continues stirring 30 minutes.It then will be anti-
It answers system to be warmed to room temperature naturally and is stirred to react overnight.
Reaction terminates, and after reaction solution is cooled to 0 DEG C plus water (5mL) is quenched.It is concentrated under reduced pressure and removes most of tetrahydrofuran,
Gained mixed liquor is extracted with ethyl acetate (25mL × 3).Merge organic phase, anhydrous sodium sulfate drying is concentrated under reduced pressure, and gained slightly produces
Object passes through column chromatography (200-300 mesh silica gel, n-hexane：Ethyl acetate=4:1) purifying obtains target product 1.0g (yields
62%).1H NMR(CDCl3)δ：7.44-7.35 (m, 5H), 5.07-4.89 (m, 4H), 3.74 (m, 1H), 3.51 (m, 1H),
2.64-2.53 (m, 2H), 2.38-2.31 (m, 1H), 1.09-1.01 (m, 6H), 0.84 (d, J=8.0Hz, 3H)
Step 2)
Under argon gas protection, compound 2 (1.0g, 1.9mmol) is dissolved in dry dichloromethane (30mL), stirring is complete
Postcooling is dissolved to 0 DEG C, is slowly added to Dess-Martin oxidants (0.97g, 2.3mmol) in batches.Drop finishes, and rises to room naturally
Temperature simultaneously continues to be stirred to react 2h.
Reaction terminates, and dichloromethane (20mL) is added and dilutes, and is filtered to remove most of insoluble solids, organic phase is respectively with full
With sodium bicarbonate (20mL), water (10mL) and saturated salt solution (10mL) washing, anhydrous sodium sulfate drying are concentrated under reduced pressure, gained
Crude product passes through column chromatography (200-300 mesh silica gel, n-hexane：Ethyl acetate=5:1) purifying obtains target product 0.51g (productions
Rate 50%).1H NMR(CDCl3)δ：8.04 (d, J=8.0Hz, 2H), 7.66 (t, J=8.0Hz, 1H), 7.52 (d, J=
8.0Hz, 2H), 5.88 (s, 1H), 5.07 (d, J=12.0Hz, 1H), 4.95 (d, J=12.0Hz, 1H), 3.81 (d, J=
4.0Hz, 1H), 3.66 (s, 1H), 3.51 (d, J=4.0Hz, 1H), 3.18 (d, J=8.0Hz, 1H), 2.94 (m, 1H), 2.38-
2.32(m,2H),2.24-2.18(m,1H),2.19(s,3H),1.93-1.86(m,1H),1.64-1.58(m,2H),1.11(s,
3H), 1.01 (d, J=8.0Hz, 3H), 0.83 (d, J=8.0Hz, 3H)13C NMR(CDCl3)δ：191.95,171.40,
160.25,134.57,134.51,129.56,128.95,127.38,81.70,75.93,64.36,63.90,61.58,
58.16,55.15,54.57,40.92,39.24,36.05,33.23,31.59,30.60,29.49,29.10,28.60,
26.37,24.54,23.72,23.32,22.66,20.23,17.42,17.29,17.17,17.03,16.95,16.50,
14.85,14.55,14.14,14.05,13.87.
Step 3)
At room temperature, compound 3 (505mg, 0.96mmol) is dissolved in acetonitrile (8mL), solid mercury dichloride is added
Reaction is stirred at room temperature overnight in (2.6g, 9.6mmol) and water (2mL).Reaction terminates, and is filtered to remove insoluble solids, mother liquid obtained to add
Ethyl acetate (100mL) dilute, respectively use saturated sodium-chloride (10mL × 3), saturated ammonium chloride (10mL × 3), water (10mL) and
Saturated salt solution (10mL) washs, and organic phase is dried with anhydrous sodium sulfate, is concentrated under reduced pressure, gained crude by column chromatography (200-
300 mesh silica gel, n-hexane：Ethyl acetate=4:1) purifying obtains target product 0.21g (yield 60%).1H NMR(CDCl3)δ：
8.04 (d, J=8.0Hz, 2H), 7.66 (t, J=8.0Hz, 1H), 7.53 (t, J=8.0Hz, 2H), 5.89 (s, 1H), 3.92
(d, J=4.0Hz, 1H), 3.53 (d, J=4.0Hz, 1H), 3.40 (d, J=12.0Hz, 1H), 3.32 (d, J=4.0Hz, 1H),
2.97-2.94 (m, 1H), 2.74 (d, J=12.0Hz, 1H), 2.40-2.16 (m, 4H), 1.59-1.55 (m, 2H), 1.33-
1.24 (m, 4H), 1.14 (s, 3H), 1.01 (d, J=8.0Hz, 3H), 0.89 (d, J=8.0Hz, 3H)13C NMR(CDCl3)δ：
191.88,171.29,160.04,134.62,134.48,129.56,128.97,127.29,81.58,73.44,66.18,
65.58,60.80,60.20,56.86,54.46,40.87,35.95,29.30,28.15,23.86,17.75,17.38,
16.87,13.83.
The synthesis of embodiment 2 C19- (Hydroxybenzylated) triptolide
At room temperature, compound 2 (53mg, 0.1mmol) is dissolved in acetonitrile (8mL), solid mercury dichloride (270m is added
G, 1.0mmol) and water (2mL), reaction is stirred at room temperature overnight.Reaction terminates, and is filtered to remove insoluble solids, mother liquid obtained plus acetic acid
Ethyl ester (50mL) dilutes, and uses saturated sodium-chloride (10mL × 3), saturated ammonium chloride (10mL × 3), water (10mL) and saturation food respectively
Brine (10mL) washs, and organic phase is dried with anhydrous sodium sulfate, is concentrated under reduced pressure, gained crude by column chromatography (200-300 mesh silicon
Glue, n-hexane：Ethyl acetate=4:1) purifying obtains target product 25m g (yield 51%).
All references mentioned in the present invention is incorporated herein by reference, independent just as each document
It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can
To be made various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims
It encloses.
Claims (10)
1. a kind of C19- is acylated the preparation method of triptolide (IV), which is characterized in that the method includes the steps：
(a) in atent solvent, under alkaline condition, with formula (I) compound and aldehyde compound R2- CHO reacts, and obtains formula
(II) compound：
(b) in atent solvent, oxidation reaction is carried out with formula (II) compound, to obtain formula (III) compound：
(c) in atent solvent, formula (III) compound deprotection group obtains formula (IV) compound：
Wherein R1For first sulfidomethyl, acetyl group, trimethylsilyl, R2For phenyl, C1-C10 alkyl, contains 1-4 at C3-C8 naphthenic base
Heteroatomic 5-10 circle heterocyclic rings base selected from N, O or S.
2. the method as described in claim 1, it is characterised in that：R1For first sulfidomethyl, R2For phenyl.
3. the method as described in claim 1, which is characterized in that in the step a), the reaction is selected from the group below
It is carried out in the presence of alkali：Lithium diisopropyl amido (LDA), n-BuLi (n-BuLi), tert-butyl lithium (t-BuLi), two silicon of hexamethyl
Base amido lithium (LiHMDS), two silicon substrate amido (NaHMDS) of hexamethyl, sodium hydride (NaH).
4. the method as described in claim 1, which is characterized in that in the step (a), the alkali and formula (I) compound
Ratio be (0.8-4.0):1, preferably (1.0-2.0):1.
5. the method as described in claim 1, which is characterized in that in the step (a), the atent solvent is selected from the group
Tetrahydrofuran and ether, preferably tetrahydrofuran.
6. the method as described in claim 1, which is characterized in that the method for oxidation used in oxidation reaction described in step (b)
It is selected from the group：Dess-Martin is aoxidized, IBX oxidations, Swern oxidations, Moffatt oxidations, MnO2Oxidation, SeO2Oxidation,
Collins is aoxidized, Jones oxidations, PCC oxidations, PDC oxidations.
7. the method as described in claim 1, which is characterized in that in the step (b), the atent solvent is selected from down
Group：Ethyl acetate, dichloromethane, chloroform, tetrahydrofuran, ether, acetonitrile, Isosorbide-5-Nitrae-dioxane, n,N-Dimethylformamide, N,
N- dimethylacetylamides, dimethyl sulfoxide, or combinations thereof.
8. the method as described in claim 1, which is characterized in that the R2It is selected from the group：Phenyl, 2- furyls, 3- furans
Base, 2- thienyls, 3- thienyls, 2- pyridyl groups, 3- pyridyl groups, 4- pyridyl groups, C1-C10 alkyl.
9. a kind of C19- is acylated the preparation method of triptolide (IV), which is characterized in that the method includes the steps：
C) in atent solvent, formula (III) compound deprotection group obtains formula (IV) compound：
Wherein, the definition of each group is as described in the appended claim 1.
10. a kind of C19- being shown below is acylated triptolide and prepares intermediate：
Wherein, X is selected from the group：-OH、O；
Wherein R1It is selected from the group：First sulfidomethyl, acetyl group, trimethylsilyl, R2For phenyl, C1-C10 alkyl, contains C3-C8 naphthenic base
There are the 1-4 heteroatomic 5-10 unit's heteroaryls for being selected from N, O or S；Dotted line indicates chemical bond or nothing.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110551170A (en) * | 2018-05-31 | 2019-12-10 | 欣凯医药化工中间体（上海）有限公司 | Synthesis method of C-19 single-acyl triptolide derivative |
| CN110551171A (en) * | 2018-05-31 | 2019-12-10 | 欣凯医药化工中间体（上海）有限公司 | preparation method of triptolide derivative |
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| CN110551170A (en) * | 2018-05-31 | 2019-12-10 | 欣凯医药化工中间体（上海）有限公司 | Synthesis method of C-19 single-acyl triptolide derivative |
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| CN110551171B (en) * | 2018-05-31 | 2021-07-27 | 欣凯医药化工中间体（上海）有限公司 | Preparation method of triptolide derivative |
| CN110551170B (en) * | 2018-05-31 | 2022-04-22 | 欣凯医药化工中间体（上海）有限公司 | Synthesis method of C-19 single-acyl triptolide derivative |
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