CN107235952A - It is a kind of to help the synthetic method for pacifying moldin skeleton - Google Patents
It is a kind of to help the synthetic method for pacifying moldin skeleton Download PDFInfo
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- CN107235952A CN107235952A CN201710550852.1A CN201710550852A CN107235952A CN 107235952 A CN107235952 A CN 107235952A CN 201710550852 A CN201710550852 A CN 201710550852A CN 107235952 A CN107235952 A CN 107235952A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
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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
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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- Y02P20/50—Improvements relating to the production of bulk chemicals
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Abstract
The invention discloses a kind of synthetic method for helping peace moldin skeleton, this method is using the compound of formula 1 as initiation material, Yuan coupling reactions of Jing Guo, and the step of removing silicon protection group two, which is converted, obtains the compound of formula 3.Simultaneously using the compound of formula 4 as initiation material, the compound of formula 6 is obtained by a Buddhist nun gram oxidation, esterification.The compound of formula 3 and the Yuan coupling reactions of compound Jing Guo of formula 6, silicon substrate protection phenolic hydroxyl group, selectively removing methoxyl group; acetylene bond is reduced, Er Yuan coupling reactions occur for 6 π electrocyclizations, activation phenolic hydroxyl group; remove silicon-based protecting group, ullmann reaction, methyl protection; Buddhist nun gram oxidation; Fu Lide-Kerafyrm thatch is acylated, and ester is hydrolyzed, with amino acid condensation; the lower hydrolysis acetylene bond of gold catalysis be ketone obtain pentamethoxyl protection help peace moldin, realize the synthesis for helping peace moldin skeleton.The synthetic route is reasonable in design, and raw material is cheap and easy to get, and operation is simple, and key reaction intermediate is easily modified, and the study on the synthesis of a variety of how ring-like xanthone class natural products can be realized using this method.
Description
Technical field
It is specifically a kind of to synthesize the synthetic method for helping peace moldin skeleton the invention belongs to organic synthesis field.
Background technology
Help the type that peace moldin is many ring type structures belonged in xanthene ketone natural products.From marine streptomyces
That isolates helps peace moldin skeleton to show good cytotoxicity to colon cancer cell and stomach cancer cell, its IC50Value reaches
0.8μM(Dong-Chan Oh et.al.,J.Nat.Prod.,2015,78,524–529).Help peace moldin Structures of Natural Products
Mainly include an xanthone ring and a chiral amino acid fragment, therefore synthesize the difficult point of the natural products and lie also in xanthone
Structure and chiral amino acid introducing.Its structure is as follows：
There is presently no the fully synthetic report to helping peace moldin natural products.And be used as similar with helping peace moldin to have
The dense fuscomycin A of natural products of structure1、A2, it is Omura groups in 1986 first from streptomyces Streptomyces
How ring-like natural products isolated cervinus, and in 1986 by the group identify its structure (Omura, S.,
J.Am.Chem.Soc.,1986,108,6088).At present, T.Ross Kelly groups and Goverdhan Metha groups complete
To dense fuscomycin A1、A2Fully synthetic report.Its structure is as follows：
Its synthetic route is as follows：
The synthetic route of T.Ross Kelly groups：
T.Ross Kelly groups in 1989 complete to the molecule it is fully synthetic first (T.Ross Kelly,
Christopher T.Jagoe, Qun Li J.Am.Chem.Soc., 1989,111,4522-4524), author uses convergence type
Route, occurs S by the 1,4-benzoquinone of double iodos and polysubstituted phenol firstNIn 2 substitution reactions, Fu for then occurring intramolecular
Moral-Kerafyrm thatch acyl reaction builds EFG rings.ABC rings are set out with the 3- hydroxylphenylethyl alcohols of protection, and tertiary fourth is introduced at its ortho position
Base amide group, and then occurs after metalation twice, carburetting that cyclization obtains isocoumarin under acid condition, with ethanol
Amine occurs annelation and obtains the tricyclic compound containing oxazolidine, and ABC rings occur after intermolecular He Ke reactions with EFG rings,
In illumination condition the dense fuscomycin A of natural products is realized by 6 π electrocyclizations2Synthesis.
The synthetic route of Kelly groups is brief, and combined coefficient is good, but reaction raw materials and reagent are related to harmful danger
Product, reactions steps are not easy to operate, are difficult amplificationization, at the same the synthesis obtain be racemization natural products, therefore can not be into
To efficiently synthesize the best practice of the dense fuscomycin of natural products.
The synthetic route of Goverdhan Metha groups：
And Goverdhan Metha groups also use the convergence type synthetic route similar to Kelly groups.First build EFG
Ring, the coupling of EFG ring and C ring fragments is being realized by Wittig reaction, and natural products is realized finally by oxazolidine ring is built
Dense fuscomycin A2Synthesis.
The synthetic route of Metha groups is not novel enough, and combined coefficient is low, and the reaction yield of especially 6 π electricity rings is very low,
It is unfavorable for a large amount of preparations of reaction.The natural products that it is also racemization that what the synthesis simultaneously was obtained, which is, therefore can not turn into efficient
The best practice of the dense fuscomycin of synthesis of natural product.
In summary, in the synthesis of above-mentioned natural products, there is problems with：
(1) reagent used in reacting is related to poisonous and harmful dangerous material reagent, and reactions steps are not easy to operate, is difficult amplification
Change.
(2) combined coefficient is low, and the reaction yield of especially 6 π electricity rings is very low, is unfavorable for a large amount of preparations of reaction.
(3) what synthesis was obtained is the natural products of racemization, is unfavorable for its pharmaceutical chemical further research.
Therefore develop a kind of succinct efficient and a large amount of synthesis of natural products can be synthesized and a variety of how ring-like xanthones are realized
The synthetic method of class natural products is significantly.
The content of the invention
In view of the above-mentioned problems existing in the prior art, it is concisely and efficiently it is an object of the invention to provide one kind and helps peace moldin
Skeleton synthetic method, and raw material is easy to derivatization, to promote the synthesis for realizing a variety of how ring-like xanthone class natural products.
For achieving the above object, the present invention is using technical scheme in detail below：
It is a kind of to help the synthetic method for pacifying moldin skeleton, it is characterised in that using the compound of formula 1 as initiation material, Jing Guo Yuan
Head coupling, the step conversion of removing silicon protection group two obtains the compound of formula 3；Simultaneously using the compound of formula 4 as initiation material, by a Buddhist nun gram
Oxidation, esterification obtain the compound of formula 6；The Yuan couplings of the compound of formula 3 and 6 compound Jing Guo of formula, silicon substrate protection phenolic hydroxyl group, selection
Property removing methoxyl group, reduction acetylene bond obtains the compound of formula 10, then occurs 6 π electrocyclizations, and activation phenolic hydroxyl group and propine generation is secondary
Yuan couplings, removing silicon-based protecting group obtains the compound of formula 12, and then occurs ullmann reaction with the compound of formula 13, by first
Base is protected, and a Buddhist nun gram oxidation, Fu Lide-Kerafyrm thatch is acylated and obtains the compound of formula 16, then hydrolyzes ester, is contracted with amino acid
Close, the lower hydrolysis acetylene bond of gold catalysis be ketone obtain pentamethoxyl protection help peace skeleton 18 compound of moldin；Specific synthesis road
Line is as follows：
A) compound of formula 1 makees catalyst in double benzonitrile palladium chlorides, cuprous iodide, tri-tert tetrafluoro boric acid phosphine be with
Body, reacts 24 hours in the mixed solvent and the triisopropylsilyl acetylene of toluene and diisopropylamine at a temperature of 110 DEG C, you can
Obtain the compound of formula 2；Wherein, the mole of the compound of formula 1 is 0.1 to 100 moles；The consumption of solvent is every mM (mmol)
The compound of the formula 1 correspondence scope of application is 10mL, wherein, the volume ratio of toluene and diisopropylamine is 5 ︰ 1；The ratio of the amount of its material is
The double benzonitrile dichloride Ba ︰ tri-tert tetrafluoro boric acid Lin ︰ cuprous iodides=︰ 5 of 100 ︰, 7 ︰ 14 of the Hua He Wu ︰ of formula 1；
B) compound of formula 2 makees solvent in tetrahydrofuran, and tetrabutyl ammonium fluoride removing silicon-based protecting group is reacted at room temperature 7 small
When, you can obtain the compound of formula 3；Wherein, the mole of the compound of formula 2 is 0.1 to 100 moles；The consumption of solvent is every mM
(mmol) compound of the formula 2 correspondence scope of application is 10mL；The ratio of the amount of its material is the ︰ of Hua He Wu ︰ tetrabutyl ammonium fluorides of formula 2=5
6；
C) compound of formula 4 is using acetonitrile and water as mixed solvent, and sodium dihydrogen phosphate is buffer, hydrogen peroxide reduction by-product
Under conditions of thing, sodium chlorite oxidation lower 0 DEG C of 24 hour of reaction, occur a Buddhist nun gram oxidation, produce the compound of formula 5；Its
In, the mole of the compound of formula 4 is 0.1 to 100 moles；The consumption of solvent is that the every mM of compound of (mmol) formula 4 correspondence is suitable
It is 10mL with scope, wherein, the volume ratio of acetonitrile and water is 5 ︰ 1；The ratio of the amount of its material is the Hua He Wu ︰ Lin acid dihydride Na ︰ of formula 4
The Ya Lv Suan Na ︰ hydrogen peroxide=︰ 150 of 100 ︰, 23 ︰ 145；
D) compound of formula 5 is solvent in DMF, and potassium carbonate is alkali, anti-at room temperature with dimethyl suflfate
5 hours are answered, the compound of formula 6 is produced；Wherein, the mole of the compound of formula 5 is 0.1 to 100 moles；The consumption of solvent is per milli
Mole compound of (mmol) formula 5 correspondence scope of application is 10mL；The ratio of the amount of its material is the Hua He Wu ︰ Tan Suan Jia ︰ sulfuric acid two of formula 5
The ︰ 21 of methyl esters=20 ︰ 10；
E) compound of formula 3 and the compound of formula 6 are using DMF and triethylamine as mixed solvent, bi triphenyl
Under the catalytic action of phosphine dichloride palladium and cuprous iodide, reacted 1 hour in 80 DEG C, Yuan couplings of Fa Sheng produce the chemical combination of formula 7
Thing；Wherein, the mole of the compound of formula 3 is 0.1 to 100 moles；The mole of the compound of formula 6 is 0.1 to 100 moles；Solvent
Consumption be that every mM of compound of (mmol) formula 6 correspondence scope of application is 10mL, wherein, DMF and three second
The volume ratio of amine is 5 ︰ 1；The ratio of the amount of its material is that the Hua He Wu ︰ bis- triphenylphosphine dichloride Ba ︰ iodate of 3 Hua He Wu ︰ formulas of formula 6 is sub-
Copper=the ︰ 2 of 13 ︰, 10 ︰ 1；
F) compound of formula 7 is using dichloromethane as solvent, under conditions of triethylamine is alkali, with triisopropylsilyl trifluoro
Methanesulfonates reacts 3 hours at 0 DEG C, and protection hydroxyl obtains the compound of formula 8；Wherein, the mole of the compound of formula 7 is 0.1 to 100
Mole；The consumption of solvent is that the every mM of compound of (mmol) formula 7 correspondence scope of application is 10mL；The ratio of the amount of its material is formula
The 7 Hua He Wu ︰ triisopropylsilyl trifluoromethanesulfonic acid Zhi ︰ triethylamines=︰ 4 of 2 ︰ 3；
H) compound of formula 8 is using dichloromethane as solvent, and boron chloride acts on the removing ester carbonyl group ortho position of lower selectivity
Methoxyl group, during -78 DEG C are slowly increased to room temperature, react 1 hour, produces the compound of formula 9；Wherein, formula 8 compound
Mole is 0.1 to 100 moles；The consumption of solvent is that the every mM of compound of (mmol) formula 8 correspondence scope of application is 10mL；Its
The ratio of the amount of material is the ︰ 11 of Hua He Wu ︰ boron chlorides of formula 8=10；
I) under conditions of palladium/barium sulfate and quinoline, reduction is used as with hydrogen using tetrahydrofuran as solvent for the compound of formula 9
Agent, reacts 0.5-2 hour, produces the compound of formula 10 at room temperature；Wherein, the mole of the compound of formula 9 is 0.1 to 100 moles；
The consumption of solvent is that the every mM of compound of (mmol) formula 9 correspondence scope of application is 10mL；The ratio of its quality is the Hua He Wu ︰ of formula 9
Palladium/Liu Suan Bei ︰ quinoline=︰ 1 of 5 ︰ 1；
J) compound of formula 10 is being used as solvent, 60 DEG C of heating water baths, in the high-pressure mercury of 500 watts of power with 1,1- dichloroethanes
Reacting 8 hours under light irradiation occurs 6 π electrocyclizations, then in DMF solution with the double (fluoroforms of N- phenyl
Alkane sulphonyl) 1 hour of imine reaction, phenolic hydroxyl group is activated, that is, obtains the compound of formula 11；Wherein, the mole of the compound of formula 10 is
0.01 to 100 moles；The consumption of solvent is that the every mM of compound of (mmol) formula 10 correspondence scope of application is 10mL；Its material
The ratio of amount is the ︰ 1 of double (fluoroform sulphonyl) imines of the Hua He Wu ︰ N- phenyl of formula 10=1；
K) compound of formula 11 is using DMF and triethylamine as mixed solvent, bis-triphenylphosphipalladium palladium dichloride and
Under the catalytic action of cuprous iodide, reacted 9 hours with propine in 80 DEG C, Fa Sheng Yuan are coupled, and obtain coupled product, then with
Tetrabutyl ammonium fluoride trihydrate reacts, and removes silicon-based protecting group, produces the compound of formula 12；Wherein, formula 11 compound is rubbed
Your amount is 0.1 to 100 moles；The consumption of solvent is that the every mM of compound of (mmol) formula 11 correspondence scope of application is 10mL, its
In, the volume ratio of DMF and triethylamine is 1 ︰ 1；The ratio of the amount of its material is the Hua He Wu ︰ bi triphenyls of formula 11
The phosphine dichloride Ba ︰ Dianization Ya Tong ︰ Bing Que ︰ tetrabutyl ammonium fluorides trihydrate=︰ 5 of 5 ︰, 1 ︰, 1 ︰ 10；
L) compound of formula 12 is solvent in DMF with the compound of formula 13, and cesium carbonate is used as alkali, protobromide
Copper reacts 2 hours as catalyst under 120 DEG C of high temperature, occur ullmann reaction, that is, obtain the compound of formula 14；Wherein, formula 12
The mole of compound is 0.1 to 100 moles；The mole of the compound of formula 13 is 0.1 to 100 moles；The consumption of solvent is every
MM compound of (mmol) formula 12 correspondence scope of application is 10mL；The ratio of the amount of its material is the chemical combination of 12 Hua He Wu ︰ formulas of formula 13
The Wu ︰ Tan Suan Se ︰ cuprous bromides=︰ 1 of 2 ︰, 3 ︰ 3；
M) compound of formula 14 is solvent in acetone, and potassium carbonate is alkali, and 2 hours are reacted at 70 DEG C with dimethyl suflfate,
Obtain the compound of formula 15；Wherein, the mole of the compound of formula 14 is 0.01 to 100 moles；The consumption of solvent is every mM
(mmol) compound of the formula 14 correspondence scope of application is 10mL；The ratio of the amount of its material is the Hua He Wu ︰ Tan Suan Jia ︰ dimethyl sulfates of formula 14
The ︰ 4 of ester=1 ︰ 2；
N) under sodium chlorite oxidation, 3 are reacted in 0 DEG C in dimethyl sulfoxide and water as mixed solvent for the compound of formula 15
Individual hour, a product for Buddhist nun gram oxidation is obtained, is then dissolved in dichloromethane solution, with oxalyl chloride and the N of catalytic amount, N- bis-
NMF is acted on, and reaction obtains chlorobenzoyl chloride product in 50 minutes at 0 DEG C；And then it is dissolved in hexafluoroisopropanol,
9 hours are reacted at room temperature, that is, obtain the compound of formula 16；Wherein, the mole of the compound of formula 15 is 0.01 to 100 moles；It is molten
The consumption of agent is that the every mM of compound of (mmol) formula 15 correspondence scope of application is 10mL, wherein, the volume of dimethyl sulfoxide and water
Than for 5 ︰ 1；The ratio of the amount of its material is the Hua He Wu ︰ Ya Lv Suan Na ︰ Cao Xian Lv ︰ N,N-dimethylformamides of formula 15=︰ of 10 ︰ 29
20 ︰ 5；
O) compound of formula 16 is acted in the in the mixed solvent of tetrahydrofuran, first alcohol and water with sodium hydroxide, in 70 DEG C of reactions
10 hours, hydrolysis methyl esters is formic acid, that is, obtains benzoic acid compounds；It is then solvent, three second in DMF
Amine is alkali, occurs condensation reaction with 2- methyl-L-serines methyl ester hydrochloride under the special condensing agent effect of card, reacts at room temperature
9 hours, that is, obtain the compound of formula 17；Wherein, the mole of the compound of formula 16 is 0.01 to 100 moles；The consumption of solvent is
The every mM of compound of (mmol) formula 16 correspondence scope of application is 10mL；The ratio of the amount of its material is the Hua He Wu ︰ tri- Yi An ︰ of formula 16
The Ka Te condensation agent ︰ 2- methyl-L-serines methyl ester hydrochloride=︰ 52 of 10 ︰, 90 ︰ 15；
P) compound of formula 17 is solvent in dichloromethane, and triphenylphosphine gold trifluoromethayl sulfonic acid ester is catalyst, in room temperature
0.5 hour of lower reaction, hydrolysis acetylene bond is ketone, and trifluoromethanesulfonic acid acidolysis gold complex obtains the compound of formula 18；Wherein, formula
The mole of 17 compounds is 0.01 to 100 moles；The consumption of solvent is that the every mM of compound of (mmol) formula 17 correspondence is applicable
Scope is 10mL；The ratio of the amount of its material be the Hua He Wu ︰ triphenylphosphines gold trifluoromethayl sulfonic acid Zhi ︰ trifluoromethanesulfonic acids of formula 17=
The ︰ 10 of 10 ︰ 1.
Beneficial effects of the present invention：
1) various reagents used in reaction involved in the present invention are simple and easy to get, commercially available.Operating procedure letter
It is single,
Requirement to reaction is relatively low, meets the requirement of technology.
2) outstanding feature of this synthetic method is that the structure of hydrogenation phenanthrene ring (CDE rings) is efficiently realized by 6 π electrocyclizations
Build, and the synthesis of target product is realized as basic fragment with linear synthetic route.
3), can be with while the synthetic route of the present invention is also the synthetic method on helping peace moldin skeleton reported first
For follow-up synthesis and pharmaceutical chemistry research, technological development provides basis.
Embodiment
The present invention is made below further in detail, intactly to illustrate.Given content includes concrete operations and reaction bar
Part and product.Product purity is identified by nuclear-magnetism.
The synthesis of the compound of formula 3：
The compound of formula 2 (16.10g, 48.14mmol) and tetrahydrofuran (160ml) are added in 250mL round-bottomed bottle, 0
DEG C when be slowly added to tetrabutyl ammonium fluoride (1.0M tetrahydrofurans, 67.4ml, 67,4mmol), be slowly increased to after adding room temperature reaction
7 hours, TLC monitoring systems reaction is complete.1N hydrochloric acid (100ml) is added at 0 DEG C, is stirred 30 minutes, tetrahydrochysene is walked in concentration rotation
Furans, ethyl acetate is extracted 3 times, merges organic phase, and distilled water is cleaned 1 time, and saturated aqueous common salt is cleaned 1 time, and organic phase is with anhydrous
Sodium sulphate dry, filter, concentration, using column chromatography (10% ethyl acetate/petroleum ether) separate the compound of formula 3 (6.7g,
78%).Rf=0.35 (20% ethyl acetate/petroleum ether).
After tested：1H NMR(400MHz,CDCl3) δ 6.56 (d, J=3.0Hz, 1H), 6.51 (d, J=3.0Hz, 1H),
5.83–5.74(m,1H),3.96(s,3H),3.74(s,3H),3.30(s,1H).
13C NMR(101MHz,CDCl3)δ155.92,149.33,142.72,114.90,109.56,103.43,81.84,
79.45,61.52,55.63.
ESI(m/z):Exact mass calcd for C10H10O3[M+Na]+:179.06；found 179.16.
The synthesis of the compound of formula 6：
The compound of formula 5 (32.63g, 98.8mmol) and N,N-dimethylformamide are added in 500mL round-bottomed bottle
(200ml), after stirring, is slowly added to potassium carbonate (6.83g, 49.4mmol) at 0 DEG C, after quickly stirring 20 minutes, delays
It is slow to add dimethyl suflfate (9.82ml, 103.74mmol), room temperature is slowly increased to, is reacted 5 hours, the reaction of TLC monitoring systems
Completely.Add saturated ammonium chloride solution (50ml) and extract reaction of going out, ethyl acetate is extracted 3 times, and distilled water is cleaned 3 times, saturated common salt
Water is cleaned 1 time, organic phase anhydrous sodium sulfate drying, is filtered, and concentration uses column chromatography (20% ethyl acetate/petroleum ether) point
From the compound of formula 6 (30.16g, 91%).Rf=0.43 (20% ethyl acetate/petroleum ether).
After tested：1H NMR(400MHz,CDCl3)δ6.46(s,2H),3.91(s,3H),3.83(s,6H).
13C NMR(101MHz,CDCl3)δ165.45,158.06(2C),151.22,123.40,120.21,117.02,
113.83,112.81,97.85(2C),56.39(2C),52.69。
The synthesis of the compound of formula 8：
The compound of formula 7 (15.86g, 42.59mmol) and dichloromethane are added in dry 250mL round-bottomed bottle
(100ml), triethylamine (23.7ml, 170.35mmol) and triisopropylsilyl trifluoro are sequentially added at 0 DEG C under nitrogen protection
Methanesulfonates (34.5ml, 127.76mmol), is stirred at 0 DEG C 4 hours, and the reaction of TLC monitoring systems is complete.Add 2N hydrochloric acid extraction
Reaction go out until the pH value of system is close to 1, dichloromethane is extracted 3 times, successively with distilled water, saturated sodium bicarbonate solution and saturation
Each 1 time of saline solution cleaning organic phase, organic phase anhydrous sodium sulfate drying is filtered, and concentration uses column chromatography (10% acetic acid second
Ester/petroleum ether) separate to obtain the compound of formula 8 (16.37g, 73%).Rf=0.61 (20% ethyl acetate/petroleum ether).
After tested：1H NMR(400MHz,CDCl3) δ 6.74 (s, 2H), 6.61 (d, J=2.9Hz, 1H), 6.49 (d, J=
2.9Hz,1H),3.91(s,3H),3.89(s,3H),3.84(s,6H),3.76(s,3H),1.35–1.25(m,3H),1.12(d,
J=7.3Hz, 18H)
13C NMR(101MHz,CDCl3)δ166.55,156.98(2C),155.40,149.90,146.65,125.98,
117.48,113.12,109.22,108.45,107.28(2C),92.30,86.63,77.32,77.00,76.68,61.16,
56.12(2C),55.55,52.55,17.87(3C),12.70(6C).
ESI(m/z):Exact mass calcd for C29H40O7SiNa[M+H]+:529.26；found 529.12.Formula
The synthesis of 9 compounds：
The compound of formula 8 (9.68g, 18.31mmol) and dichloromethane are added in dry 250mL round-bottomed bottle
(80ml), system is placed at a temperature of -78 DEG C, and then in 15 minutes it is slow be added dropwise boron chloride (1.0M hexamethylenes,
17.6ml, 17.64mmol) into system, after being stirred 10 minutes at -78 DEG C, -78 DEG C of Cryo Equipments are removed, system is slow
Recover to room temperature, react 1 hour, the reaction of TLC monitoring systems is complete under nitrogen protection.System is cooled to 0 DEG C, slow drop
Plus 1N hydrochloric acid (20ml) extracts reaction of going out, stirred 10 minutes at 0 DEG C.Dichloromethane is extracted 3 times, is eaten successively with distilled water, saturation
Salt solution each 1 time of organic phase of cleaning, organic phase anhydrous sodium sulfate drying is filtered, concentration, using column chromatography (5% ethyl acetate/
Petroleum ether) separate to obtain the compound of formula 9 (8.51g, 91%).Rf=0.40 (10% ethyl acetate/petroleum ether).
After tested：1H NMR(400MHz,CDCl3) δ 11.58 (s, 1H), 6.79 (d, J=1.4Hz, 1H), 6.60 (d, J=
2.9Hz, 1H), 6.57 (d, J=1.4Hz, 1H), 6.50 (d, J=3.0Hz, 1H), 3.96 (s, 3H), 3.89 (s, 6H), 3.76
(s, 3H), 1.29 (d, J=7.7Hz, 3H), 1.11 (d, J=7.4Hz, 18H) ..
13C NMR(126MHz,CDCl3)δ171.25,163.29,160.52,155.44,149.94,146.93,
129.95,117.32,113.27,109.51,108.64,105.35,103.10,91.94,88.74,61.13,56.33,
55.60,52.53,17.89(3C),12.75(6C).
ESI(m/z):Exact mass calcd for C28H38O7Si[M+H]+:515.25；found 515.28.
The synthesis of the compound of formula 10：
The compound of formula 9 (6.51g, 12.65mmol) and tetrahydrofuran are added in round-bottomed bottles of the 200mL with branch mouthful
(63ml), is separately added into palladium/barium sulfate (1.30g, 0.2w/w, 5%Pd) and quinoline (651ul, 0.1w/w), stirs successively
Afterwards, quickly the air in system is taken away under vacuum conditions, is replaced as nitrogen, in last time displacement gas, by system control
System under vacuum conditions, inserts hydrogen balloon, has now been replaced into hydrogen in system.0.5-2 hour, TLC are reacted at room temperature
Monitoring system reaction is complete.Diatomite filters out palladium/barium sulfate, and with ethyl acetate rinse filter cake 3 times, the filtrate of merging uses 2N salt
Sour (10ml), distilled water and saturated aqueous common salt clean organic phase each 1 time, and organic phase anhydrous sodium sulfate drying is filtered, concentration,
10 compounds (6.1g, 93%) are separated to obtain using column chromatography (5% ethyl acetate/petroleum ether).Rf=0.50 (10% acetic acid second
Ester/petroleum ether).
After tested：1H NMR(300MHz,CDCl3) δ 11.49 (s, 1H), 6.82 (d, J=12.3Hz, 1H), 6.56-6.48
(m, 2H), 6.38 (d, J=2.9Hz, 1H), 6.31 (d, J=1.5Hz, 1H), 6.29 (d, J=3.0Hz, 1H), 3.92 (s,
3H), (d, J=7.2Hz, the 18H) of 3.77 (s, 3H), 3.57 (s, 3H), 3.52 (s, 3H), 1.34-1.24 (m, 3H), 1.12
13C NMR(101MHz,CDCl3)δ171.35,163.43,160.05,155.15,149.87,143.96,
143.20,131.25,129.72,129.08,110.79,107.36,105.99,103.05,101.52,60.78,55.77,
55.42,52.38,17.89(3C),12.77(6C)。
The synthesis of the compound of formula 11：
Weigh the compound of formula 10 (2x1.5g, 2.90mmol) to be respectively placed in 2 clean light reaction pipes (quartz ampoule), nitrogen
1,1- dichloroethanes, 2 × 60ml (25mg/ml) of dry and bubbling deoxygenation is added under gas shielded, light reaction pipe is placed in after shaking up
60 DEG C of water bath heating device, irradiates 8 hours in high-pressure sodium lamp photochemical reactor, closes Photoreactor and takes out quartz
Pipe is complete in the lower TLC monitoring system reactions of nitrogen protection.The system for the treatment of is cooled to room temperature, and concentrated solvent obtains 6 π electrocyclizations and slightly produced
Thing, uses the π electrocyclization products of column chromatography for separation 6.6 π electrocyclization products of gained are then dissolved in N,N-dimethylformamide
In (18ml), sequentially add double (fluoroform sulphonyl) imines (1.27g, 3.54mmol) of N- phenyl and potassium carbonate (538.2mg,
3.89mmol), react at room temperature 2 hours, the reaction of TLC monitoring systems is complete.Saturated ammonium chloride solution (10ml) extraction is added to go out
Reaction, ethyl acetate is extracted 3 times, and distilled water is cleaned 3 times, and saturated aqueous common salt is cleaned 1 time, organic phase anhydrous sodium sulfate drying,
Filtering, concentration, the compound of formula 11 (2.09g, 55%) is separated to obtain using column chromatography (2% ethyl acetate/petroleum ether).Rf=0.60
(10% ethyl acetate/petroleum ether).
After tested：1H NMR(500MHz,CDCl3)δ6.96(s,1H),6.47(s,1H),3.95(s,3H),3.78(d,J
=1.3Hz, 6H), 3.45 (s, 3H), 3.22 (s, 1H), 2.76 (s, 1H), 2.57 (s, 1H), 2.23 (s, 1H), 1.37-1.29
(m, 3H), 1.15 (d, J=7.4Hz, 18H)
13C NMR(126MHz,CDCl3)δ164.32,156.60,153.51,149.96,144.99,143.99,
141.05,134.46,125.83,120.32,118.5,114.52,113.61,102.86,60.90,60.81,55.99,
52.67,30.70,22.78,17.91(3C),12.84(6C).
ESI(m/z):Exact mass calcd for C29H39F3O9SSi[M+Na]+:671.19；found 670.95.
The synthesis of the compound of formula 12：
The compound of formula 11 (3.07g, 4.7mmol) is weighed in Schlenk bottles dry of 100mL, bi triphenyl phosphine is added
Palladium chloride (660mg, 0.94mmol) and cuprous iodide (179mg, 0.94mmol), add and dry and freeze under nitrogen protection
The DMF (30ml) and triethylamine (30ml) of deoxygenation, add propine (1M N, N- dimethyl formyls after shaking up
Amine, 9.4ml, 9.4mmol), system is heated to 90 DEG C of 9-15 hours of reaction, the lower TLC monitoring systems of nitrogen protection have been reacted
Entirely.Cooling system adds tetrabutyl ammonium fluoride trihydrate (1.48g, 4.7mmol), is stirred at room temperature 10 points to room temperature
Clock, TLC monitoring systems reaction is complete.Add saturated ammonium chloride solution (20ml) and extract reaction of going out, ethyl acetate is extracted 3 times, distillation
Water is cleaned 3 times, and saturated aqueous common salt is cleaned 1 time, organic phase anhydrous sodium sulfate drying, is filtered, and concentration uses column chromatography (30%
Ethyl acetate/petroleum ether) separate to obtain the compound of formula 12 (1.27g, 71%).Rf=0.43 (40% ethyl acetate/petroleum ether).
After tested：1H NMR(400MHz,CDCl3)δ7.02(s,1H),6.51(s,1H),3.92(s,3H),3.73(s,
3H),3.71(s,3H),3.40(s,3H),3.07(s,1H),2.66(s,1H),2.46(s,1H),2.21(s,1H),2.00(s,
3H).
13C NMR(101MHz,CDCl3)δ168.35,154.37,154.04,149.16,142.40,137.11,
133.42,129.17,125.10,124.69,119.69,113.38,97.76,89.17,76.65,61.51,60.26,
55.83,52.23,29.85,22.95,4.28.
HRMS(m/z):Exact mass calcd for C22H22O6Na[M]+:382.1416；found 382.1418.
The synthesis of the compound of formula 14：
The compound of formula 12 (419.6mg 1.10mmol), formula 13 are separately added into successively in Schlenk bottles dry of 100mL
Compound (380.3mg, 1.64mmol), cesium carbonate (536.3mg, 1,65mmol) and cuprous bromide (78.6mg, 0.55mmol),
The DMF (18ml) dried and freeze deoxygenation is added under nitrogen protection, and system is heated to 120 DEG C of reactions 2
Individual hour, TLC monitoring systems reaction has residue.Cooling system adds 1N hydrochloric acid (10ml) liquid and extracts go out reaction, acetic acid second to room temperature
Ester is extracted 3 times, and distilled water is cleaned 3 times, and saturated aqueous common salt is cleaned 1 time, organic phase anhydrous sodium sulfate drying, is filtered, and concentration makes
The compound (158mg, 27%, y of formula 14 is separated to obtain with column chromatography (7% ethyl acetate/dichloromethane)brsm=65%).Rf=
0.80 (7% ethyl acetate/dichloromethane).
After tested：1H NMR(500MHz,CDCl3)δ12.06(s,1H),10.50(s,1H),7.09(s,1H),6.99(d,
J=8.9Hz, 1H), 6.57 (s, 1H), 6.22 (d, J=8.9Hz, 1H), 3.95 (s, 3H), 3.86 (s, 3H), 3.76 (s, 3H),
3.73(s,3H),3.47(s,3H),3.21(s,1H),2.74(s,1H),2.54(s,1H),2.24(s,1H),2.05(s,3H).
13C NMR(126MHz,CDCl3)δ194.47,168.19,155.03,153.80,153.55,153.15,
148.02,143.56,142.98,141.54,135.83,129.34,125.46,124.28,121.03,119.57,118.90,
112.03,105.05,103.31,89.86,77.20,61.75,60.83,56.70,56.32,52.42,29.99,22.95,
4.54.
HRMS(m/z):Exact mass calcd for C30H28O9Na[M]+:532.1733；found 532.1739.
The synthesis of the compound of formula 15：
The compound of formula 14 (420mg, 0.789mmol) and acetone (16ml) are added in 100mL round-bottomed bottle, is then added
Potassium carbonate (218mg, 1.58mmol), after stirring, adds dimethyl suflfate (299ul, 3.15mmol), is heated to reflux, instead
Answer 2 hours, the reaction of TLC monitoring systems is complete.Room temperature is cooled to, diatomite filters out filter residue, and ethyl acetate rinse filter residue is closed
And organic phase, concentration is spin-dried for, using column chromatography (30% ethyl acetate/petroleum ether) separate the compound of formula 15 (378.1mg,
88%).Rf=0.42 (20% ethyl acetate/petroleum ether).
After tested：1H NMR(500MHz,CDCl3) δ 10.55 (s, 1H), 7.07 (s, 1H), 7.04 (d, J=9.1Hz,
1H), 6.58 (d, J=9.1Hz, 1H), 6.50 (s, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 3.86 (s, 3H), 3.76 (s,
3H),3.72(s,3H),3.44(s,3H),3.20(s,1H),2.72(s,1H),2.53(s,1H),2.22(s,1H),2.04(s,
3H).
13C NMR(126MHz,CDCl3)δ188.92,168.19,154.96,153.73,151.71,151.60,
148.77,148.48,142.99,141.11,135.55,129.36,125.39,124.44,120.95,120.72,118.55,
118.09,112.40,102.77,89.65,77.20,62.12,61.58,60.75,56.47,56.28,52.36,30.02,
22.87,4.50.
HRMS(m/z):Exact mass calcd for C31H30O9Na[M]+:546.1890；found 546.1906.
The synthesis of the compound of formula 16：
The compound of formula 15 (378.1mg, 0.692mmol) and acetonitrile (12.5ml), stirring are added in 50ml round-bottomed bottle
The hydrate of sodium dihydrogen phosphate two (54mg is dissolved in 2,5ml water, 0.346mmol), hydrogen peroxide are added after uniform at 0 DEG C
(208ul, 30%v/v, 2.075mmol), sodium chlorite (181.5mg, 2.01mmol), it is slow to recover to room temperature, react 4 small
When, obtain benzoic acid compounds.In dry 50mlSchlenk bottles, crude product benzoic acid compounds are dissolved in dry
Dichloromethane (7ml), addition DMF (27ul, 0.35mmol) at 0 DEG C, oxalyl chloride (117ul,
1.38mmol), react 50 minutes at this temperature, concentration in vacuo solvent, by gained crude product benzoyl under nitrogen protection
Chlorine is dissolved in hexafluoroisopropanol (2.5ml), reacts at room temperature 14 hours, and the reaction of TLC monitoring systems is complete.Removed under vacuum state
Hexafluoroisopropanol is removed, the compound of formula 16 (211.6mg, 56%) is separated to obtain using column chromatography (30% ethyl acetate/petroleum ether).Rf
=0.56 (50% ethyl acetate/petroleum ether).
After tested：1H 1H NMR(500MHz,CDCl3) δ 7.30 (d, J=9.2Hz, 1H), 7.24 (d, J=9.2Hz,
1H),7.10(s,1H),4.03(s,3H),3.97(s,3H),3.94(s,3H),3.93(s,3H),3.60(s,3H),3.49(s,
3H),3.37(s,1H),2.81(s,1H),2.55(s,1H),2.32(s,1H),2.06(s,3H).
13C NMR(126MHz,CDCl3)δ175.42,168.07,155.44,154.20,149.99,149.66,
149.42,148.82,142.58,139.69,139.66,129.38,125.14,123.61,121.36,120.52,119.48,
118.42,115.95,112.46,90.25,76.64,62.12,61.81,61.75,61.06,57.25,52.47,29.77,
23.58,4.56.
HRMS(m/z):Exact mass calcd for C31H328O9Na[M]+:544.1733；found 544.1740.
The synthesis of the compound of formula 17：
The compound of formula 16 (125mg, 0.23mmol), tetrahydrofuran (2ml), methanol are added in clean 25mL round-bottomed bottles
(2ml), after after the dissolving completely of the compound of formula 16, adds 2M sodium hydroxides (320mg is dissolved in 4ml water), system is heated to
70 DEG C, reacted at 70 DEG C 18 hours, the reaction of TLC monitoring systems is complete.The system for the treatment of is cooled to room temperature, adds the acidifying of 2N hydrochloric acid
To system PH close to 1, ethyl acetate is extracted 3 times, and respectively No. 1 machine of cleaning is dry with anhydrous sodium sulfate for distilled water and saturated aqueous common salt
It is dry, filter, concentration.Under nitrogen protection, by gained crude product and 2- methyl-L-serines (159.2mg, 1.196mmol), card
Special condensing agent (153mg, 0.345mmol), triethylamine (288ul, 2.07mmol) is dissolved in N,N-dimethylformamide (5ml)
In, 7 hours are reacted at room temperature, the reaction of TLC monitoring systems is complete, add 1N hydrochloric acid (10ml) liquid and extract reaction of going out, ethyl acetate extraction
Take 3 times, distilled water is cleaned 3 times, saturated aqueous common salt is cleaned 1 time, organic phase anhydrous sodium sulfate drying, filter, concentration uses post
Chromatogram (100% ethyl acetate) separates to obtain the compound of formula 17 (51.4mg, 35%).Rf=0.45 (100% ethyl acetate).
After tested：1H NMR(500MHz,CDCl3) δ 7.30 (d, J=9.2Hz, 1H), 7.23 (d, J=9.1Hz, 1H),
7.11 (s, 1H), 6.81 (s, 1H), 4.40 (dd, J=11.5,4.5Hz, 1H), 4.04 (s, 3H), 3.97 (s, 3H), 3.97-
3.93(m,1H),3.92(s,3H),3.83(s,3H),3.63(s,3H),3.52(s,3H),3.33(s,2H),2.77(s,1H),
2.59(s,1H),2.31(s,1H),2.06(s,3H),1.69(s,3H)...
13C NMR(126MHz,CDCl3)δ175.50,173.77,167.03,155.31,154.19,150.21,
149.80,149.60,149.20,142.44,139.84,139.72,132.33,125.55,123.88,121.58,120.70,
120.00,118.59,116.02,112.39,90.42,65.86,63.10,61.99,61.79,61.69,61.42,57.47,
52.94,29.87,23.71,19.68,4.42.
ESI(m/z):Exact mass calcd for C34H33NO11Na[M]+:645.22；found 645.99.
The synthesis of the compound of formula 18：
The compound of formula 17 (15mg, 0.023mmol) is added in clean 10ml round-bottomed flasks, dichloromethane (2ml) is treated
After the dissolving completely of the compound of formula 17, the golden trifluoromethayl sulfonic acid ester of addition triphenylphosphine well prepared in advance (1.4mg,
0.0023mmol), and trifluoromethanesulfonic acid (2ul, 0.023mmol), 1 hour is reacted at room temperature, and TLC monitoring systems have been reacted
Entirely.Add triethylamine (2ml) and extract reaction of going out, diatomite filtering filter residue, ethyl acetate rinse filter cake merges organic phase, and concentration makes
The compound of formula 18 (9.0mg, 58%) is separated to obtain with column chromatography (80% ethyl acetate/petroleum ether).Rf=0.44 (5% methanol/
Dichloromethane).
After tested：1H NMR(500MHz,CDCl3) δ 7.30 (d, J=9.1Hz, 1H), 7.23 (d, J=9.1Hz, 1H),
6.93 (s, 1H), 4.75 (d, J=8.7Hz, 1H), 4.16 (d, J=8.8Hz, 1H), 4.03 (s, 3H), 3.98 (s, 3H), 3.93
(s,3H),3.84(s,2H),3.81(s,3H),3.60(s,3H),3.47(s,3H),3.40(s,1H),2.79(s,1H),2.65
(s,1H),2.34(s,1H),2.18(s,3H),1.65(s,3H).
13C NMR(126MHz,CDCl3)δ205.51,175.42,173.71,164.02,157.86,154.24,
150.29,149.61,149.58,149.26,143.57,139.75,139.67,134.46,123.72,122.93,121.97,
120.67,119.99,118.64,116.10,112.39,77.25,77.20,77.00,76.75,76.10,74.53,61.98,
61.82,61.68,61.15,57.52,52.61,47.96,30.08,29.39,24.75,23.77。
Claims (1)
1. a kind of help the synthetic method for pacifying moldin skeleton, it is characterised in that using the compound of formula 1 as initiation material, Jing Guo Yuan heads
Coupling, the step conversion of removing silicon protection group two obtains the compound of formula 3；Simultaneously using the compound of formula 4 as initiation material, by a Buddhist nun gram oxygen
Change, esterification obtains section type 6；Yuan couplings of the compound of formula 3 and 6 compound Jing Guo of formula, silicon substrate protection phenolic hydroxyl group, selectivity is de-
Except methoxyl group, reduction acetylene bond obtains the compound of formula 10, then occurs 6 π electrocyclizations, and with propine Er Yuan head occurs for activation phenolic hydroxyl group
Coupling, removing silicon-based protecting group obtains the compound of formula 12, Ullmann couplings and then occurs with the compound of formula 13, by methyl
Protection, Buddhist nun gram oxidation, Fu Lide-Kerafyrm thatch is acylated and obtains the compound of formula 16, then hydrolyzes ester, and amino acid condensation,
The lower hydrolysis acetylene bond of gold catalysis is ketone, and obtain pentamethoxyl protection helps peace skeleton 18 compound of moldin；Specific synthetic route
It is as follows：
A) compound of formula 1 makees catalyst in double benzonitrile palladium chlorides, cuprous iodide, and tri-tert tetrafluoro boric acid phosphine is part,
The in the mixed solvent of toluene and diisopropylamine is reacted 24 hours with triisopropylsilyl acetylene at a temperature of 110 DEG C, you can obtained
The compound of formula 2；Wherein, the mole of the compound of formula 1 is 0.1 to 100 moles；The consumption of solvent is every mM of compound of formula 1
The correspondence scope of application is 10mL, wherein, the volume ratio of toluene and diisopropylamine is 5 ︰ 1；The ratio of the amount of its material is the chemical combination of formula 1
The double benzonitrile dichloride Ba ︰ tri-tert tetrafluoro boric acid Lin ︰ cuprous iodides=︰ 5 of 100 ︰, 7 ︰ 14 of Wu ︰；
B) compound of formula 2 makees solvent in tetrahydrofuran, and tetrabutyl ammonium fluoride removing silicon-based protecting group reacts at room temperature 7 hours, i.e.,
The compound of formula 3 can be obtained；Wherein, the mole of the compound of formula 2 is 0.1 to 100 moles；The consumption of solvent is every mM (mmol)
The compound of the formula 2 correspondence scope of application is 10mL；The ratio of the amount of its material is the ︰ 6 of Hua He Wu ︰ tetrabutyl ammonium fluorides of formula 2=5；
C) compound of formula 4 is using acetonitrile and water as mixed solvent, and sodium dihydrogen phosphate is buffer, hydrogen peroxide reduction accessory substance
Under the conditions of, sodium chlorite oxidation lower 0 DEG C of 24 hour of reaction, occur a Buddhist nun gram oxidation, produce the compound of formula 5；Wherein, formula
The mole of 4 compounds is 0.1 to 100 moles；The consumption of solvent is that the every mM of compound of formula 4 correspondence scope of application is
10mL, wherein, the volume ratio of acetonitrile and water is 5 ︰ 1；The ratio of the amount of its material is the Hua He Wu ︰ Lin acid dihydride Na ︰ chlorous acid of formula 4
The Na ︰ hydrogen peroxide=︰ 150 of 100 ︰, 23 ︰ 145；
D) compound of formula 5 is solvent in DMF, and potassium carbonate is alkali, and 5 are reacted at room temperature with dimethyl suflfate
Individual hour, produce the compound of formula 6；Wherein, the mole of the compound of formula 5 is 0.1 to 100 moles；The consumption of solvent is per mmoles
Your compound of the formula 5 correspondence scope of application is 10mL；The ratio of the amount of its material be the Hua He Wu ︰ Tan Suan Jia ︰ dimethyl suflfates of formula 5=
The ︰ 21 of 20 ︰ 10；
E) compound of formula 3 and the compound of formula 6 are using DMF and triethylamine as mixed solvent, bi triphenyl phosphine two
Under the catalytic action of palladium bichloride and cuprous iodide, reacted 1 hour in 80 DEG C, Yuan couplings of Fa Sheng produce the compound of formula 7；Its
In, the mole of the compound of formula 3 is 0.1 to 100 moles；The mole of the compound of formula 6 is 0.1 to 100 moles；The consumption of solvent
It is 10mL for the every mM of compound of formula 6 correspondence scope of application, wherein, the volume ratio of DMF and triethylamine is
5 ︰ 1；The ratio of the amount of its material is the Hua He Wu ︰ bis- triphenylphosphine dichloride Ba ︰ cuprous iodides of 3 Hua He Wu ︰ formulas of formula 6=︰ of 13 ︰, 10 ︰ 1
2；
F) compound of formula 7 is using dichloromethane as solvent, under conditions of triethylamine is alkali, with triisopropylsilyl fluoroform sulphur
Acid esters reacts 3 hours at 0 DEG C, and protection hydroxyl obtains the compound of formula 8；Wherein, the mole of the compound of formula 7 is rubbed for 0.1 to 100
You；The consumption of solvent is that the every mM of compound of formula 7 correspondence scope of application is 10mL；The ratio of the amount of its material is the Hua He Wu ︰ of formula 7
The triisopropylsilyl trifluoromethanesulfonic acid Zhi ︰ triethylamines=︰ 4 of 2 ︰ 3；
H) compound of formula 8 is using dichloromethane as solvent, and boron chloride acts on the methoxy at the removing ester carbonyl group ortho position of lower selectivity
Base, during -78 DEG C are slowly increased to room temperature, react 1 hour, produces the compound of formula 9；Wherein, mole of the compound of formula 8
Measure as 0.1 to 100 moles；The consumption of solvent is that the every mM of compound of formula 8 correspondence scope of application is 10mL；The amount of its material
Than for the ︰ 11 of Hua He Wu ︰ boron chlorides of formula 8=10；
I) under conditions of palladium/barium sulfate and quinoline, reducing agent, room are used as with hydrogen using tetrahydrofuran as solvent for the compound of formula 9
Temperature lower 0.5-2 hour of reaction, produce the compound of formula 10；Wherein, the mole of the compound of formula 9 is 0.1 to 100 moles；Solvent
Consumption be that every mM of compound of formula 9 correspondence scope of application is 10mL；The ratio of its quality is the Hua He Wu ︰ palladiums of formula 9/Liu Suan Bei ︰
The ︰ 1 of quinoline=5 ︰ 1；
J) compound of formula 10 is being used as solvent, 60 DEG C of heating water baths, in the high-pressure sodium lamp photograph of 500 watts of power with 1,1- dichloroethanes
Penetrating 8 hours of lower reaction occurs 6 π electrocyclizations, then in DMF solution with double (the fluoroform sulphurs of N- phenyl
Acyl) 1 hour of imine reaction, phenolic hydroxyl group is activated, that is, obtains the compound of formula 11；Wherein, the mole of the compound of formula 10 is 0.01
To 100 moles；The consumption of solvent is that the every mM of compound of formula 10 correspondence scope of application is 10mL；The ratio of the amount of its material is formula
The ︰ 1 of double (fluoroform sulphonyl) imines of 10 Hua He Wu ︰ N- phenyl=1；
K) compound of formula 11 is using DMF and triethylamine as mixed solvent, bis-triphenylphosphipalladium palladium dichloride and iodate
Under cuprous catalytic action, reacted 9 hours with propine in 80 DEG C, Yuan couplings of Fa Sheng obtain coupled product, then with four fourths
Base ammonium fluoride trihydrate reacts, and removes silicon-based protecting group, produces the compound of formula 12；Wherein, the mole of the compound of formula 11
For 0.1 to 100 moles；The consumption of solvent is that the every mM of compound of formula 11 correspondence scope of application is 10mL, wherein, N, N- diformazans
The volume ratio of base formamide and triethylamine is 1 ︰ 1；The ratio of the amount of its material is the Hua He Wu ︰ bis- triphenylphosphine dichloride Ba ︰ of formula 11
The Dianization Ya Tong ︰ Bing Que ︰ tetrabutyl ammonium fluorides trihydrate=︰ 5 of 5 ︰, 1 ︰, 1 ︰ 10；
L) compound of formula 12 is solvent in DMF with the compound of formula 13, and cesium carbonate is made as alkali, cuprous bromide
For catalyst, 2 hours are reacted under 120 DEG C of high temperature, occurs ullmann reaction, that is, obtains the compound of formula 14；Wherein, the chemical combination of formula 12
The mole of thing is 0.1 to 100 moles；The mole of the compound of formula 13 is 0.1 to 100 moles；The consumption of solvent is per mmoles
Your compound of the formula 12 correspondence scope of application is 10mL；The ratio of the amount of its material is the Hua He Wu ︰ Tan Suan Se ︰ of 12 Hua He Wu ︰ formulas of formula 13
Cuprous bromide=the ︰ 1 of 2 ︰, 3 ︰ 3；
M) compound of formula 14 is solvent in acetone, and potassium carbonate is alkali, and 2 hours are reacted at 70 DEG C with dimethyl suflfate, are produced
To the compound of formula 15；Wherein, the mole of the compound of formula 14 is 0.01 to 100 moles；The consumption of solvent is every mM of formula 14
The compound correspondence scope of application is 10mL；The ratio of the amount of its material is the Hua He Wu ︰ Tan Suan Jia ︰ dimethyl suflfates of formula 14=︰ 4 of 1 ︰ 2；
N) compound of formula 15 in dimethyl sulfoxide and water as mixed solvent, it is 3 small in 0 DEG C of reaction under sodium chlorite oxidation
When, a product for Buddhist nun gram oxidation is obtained, is then dissolved in dichloromethane solution, with oxalyl chloride and the N of catalytic amount, N- dimethyl
Formamide is acted on, and reaction obtains chlorobenzoyl chloride product in 50 minutes at 0 DEG C；And then it is dissolved in hexafluoroisopropanol, in room temperature
9 hours of lower reaction, that is, obtain the compound of formula 16；Wherein, the mole of the compound of formula 15 is 0.01 to 100 moles；Solvent
Consumption is that the every mM of compound of formula 15 correspondence scope of application is 10mL, wherein, the volume ratio of dimethyl sulfoxide and water is 5 ︰ 1；Its
The ratio of the amount of material is the Hua He Wu ︰ Ya Lv Suan Na ︰ Cao Xian Lv ︰ N,N-dimethylformamides of formula 15=︰ 5 of 10 ︰, 29 ︰ 20；
O) compound of formula 16 is acted in the in the mixed solvent of tetrahydrofuran, first alcohol and water with sodium hydroxide, and 10 are reacted at 70 DEG C
Hour, hydrolysis methyl esters is formic acid, that is, obtains benzoic acid compounds；It is then solvent in DMF, triethylamine is
Alkali, occurs condensation reaction with 2- methyl-L-serines methyl ester hydrochloride under the special condensing agent effect of card, 9 is reacted at room temperature
Hour, that is, obtain the compound of formula 17；Wherein, the mole of the compound of formula 16 is 0.01 to 100 moles；The consumption of solvent is per milli
Mole compound of the formula 16 correspondence scope of application is 10mL；The ratio of the amount of its material is that formula 16 changes the second amine ︰ Ka Te condensations of conjunction thing ︰ tri-
The Ji ︰ 2- methyl-L-serines methyl ester hydrochloride=︰ 52 of 10 ︰, 90 ︰ 15；
P) compound of formula 17 is solvent in dichloromethane, and triphenylphosphine gold trifluoromethayl sulfonic acid ester is catalyst, at room temperature instead
Answer 0.5 hour, hydrolysis acetylene bond is ketone, trifluoromethanesulfonic acid matter solution gold complex obtains the compound of formula 18；Wherein, formula 17 is changed
The mole of compound is 0.01 to 100 moles；The consumption of solvent is that the every mM of compound of formula 17 correspondence scope of application is 10mL；
The ratio of the amount of its material is the Hua He Wu ︰ triphenylphosphines gold trifluoromethayl sulfonic acid Zhi ︰ trifluoromethanesulfonic acids of formula 17=︰ 10 of 10 ︰ 1.
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| CN108047186B (en) * | 2018-02-02 | 2021-04-20 | 华东师范大学 | Method for synthesizing benastatin G |
| CN108558899A (en) * | 2018-05-16 | 2018-09-21 | 华东师范大学 | A kind of Cali's xanthene mycin A glycosyls ligand and its intermediate and preparation method |
| CN108558899B (en) * | 2018-05-16 | 2021-02-26 | 华东师范大学 | California xanthene mycin A glycosyl ligand, intermediate and preparation method thereof |
| CN109320527A (en) * | 2018-11-12 | 2019-02-12 | 中国医学科学院医药生物技术研究所 | Deer chromomycin (cervinomycin) B1, B2, B3, B4 and its production method and application |
| CN109320527B (en) * | 2018-11-12 | 2020-08-28 | 中国医学科学院医药生物技术研究所 | Cervidomycin (Cervinomycin) B1, B2, B3 and B4, and production method and application thereof |
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