CN108530515A - The preparation method of natural products BE-43547 ring-type parent nucleus - Google Patents
The preparation method of natural products BE-43547 ring-type parent nucleus Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0205—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof
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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
- 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 relates to the preparation methods of the cyclic annular parent nucleus of natural products BE 43547.The present invention is using sulfonamide in propionyl camphor as starting material, and by 15 step linear steps, asymmetric syntheses BE 43547 cyclic annular parent nucleus, synthetic route stereoselectivity provided by the invention is high, at low cost, is easy to industrialized production.
Description
Technical field
The present invention relates to a kind of synthesis preparation methods of natural products BE-43547 ring-type parent nucleus, belong to pharmaceutical synthesis neck
Domain.
Background technology
BE-43547 is by Streptothrix Espy A43547（Streptomyces）It generates, a series ofization with active anticancer
Close the general name of object.BE-43547 series compounds are a kind of include 17 membered rings cyclic annular lipopeptide compound.
According to the difference of R group by Compound nomenclature be BE-43547A1、BE-43547A2、BE-43547B1、BE-43547B2、
BE-43547B3、BE-43547 C1And BE-43547C2Seven natural products, general structure are shown in Fig. 1.BE-43547 series chemical combination
Object has similarity with antibiotic Vinylamycin and with anti-cancer active compound Rakicidins in structure.These chemical combination
Object is all macrocyclic ester peptides natural product, all contains a kind of non-natural amino acid 4- amino -2,4- Pentadienamide structure fragment.
According to the report, BE-43547 series compounds have inhibition to live in the cancer cells such as P388, colon26, DLD-1, PC-13 and MKN-45
Property.2016, Poulsen et al. probed into BE-43547A1、BE-43547A2Withent-BE-43547A1To pancreatic cancer cell
The cell activity of Panc-1, wherein IC under the conditions of normoxia50It is 1.6 ~ 3.2 μM, and under anoxic conditions
IC50It is increased to 41 ~ 53 nM.With BE-43547A2For, BE-43547A2It is thin under anoxic to pancreatic cancer cell Panc-1
Cellular toxicity is 60 times under normoxic conditions.And anoxic is the essential characteristic of many solid tumors, and with the transfer and change of tumour
It is related to treat tolerance.Therefore, research is as BE-43547, the compound with hypoxemia selection cytotoxicity, for cancer
Therapy study is very important.The source of BE-43547 limits its further research in anticancer aspect.
(Nature Chemistry, 2017,9,264-272) reports BE-43547A currently, document1Enantiomerism
The synthetic method of body.Since the stereoselectivity of the literature method of above-mentioned report is poor, and need to prepare liquid phase separation compound, because
This is unsuitable for amplification synthesis.The synthetic method of the present invention is using sulfonamide in propionyl camphor as starting material, by 15 step linear steps
Suddenly, asymmetric syntheses BE-43547 ring-type parent nucleus, synthetic route stereoselectivity provided by the invention is high, at low cost, is easy to
Industrialized production.
Invention content
The present invention provides a kind of new preparation method of natural products BE-43547 ring-type parent nucleus, synthetic route is as follows：
Wherein, the R of compound 11,12,13,7,15,6,16,4,3,2,11For 2 to 20 carbon alkyl.
Wherein, the R of compound 11,12,13,7,15,6,16,4,3,2,11For 2 alkyl to 20 carbon.
A kind of intermediate 6 for synthesizing BE-43547,
Wherein, R in compound 61For 2 alkyl to 20 carbon.
A kind of intermediate 16 for synthesizing BE-43547,
Wherein, R in compound 161For 2 alkyl to 20 carbon.
A kind of intermediate 3 for synthesizing BE-43547,
Wherein, R in compound 31For 2 alkyl to 20 carbon.
A kind of intermediate 2 for synthesizing BE-43547,
Wherein, R in compound 31For 2 alkyl to 20 carbon.
A method of the intermediate 16 described in synthesis claim 3, which is characterized in that the compound 6 of highly basic and nitrogen oxa- three
First cyclics (II), reaction generates compound 16, mole of highly basic and compound 6 in atent solvent under basic conditions
Equivalent proportion is 0.2: 1 ~ 1.1 :1,
Wherein, R in compound 6 and 161For 2 alkyl to 20 carbon.
A kind of method of above-mentioned synthetic intermediate 16, which is characterized in that nitrogen oxa- ternary cyclics (II) as shown,
Wherein R in formula (II)2For benzenesulfonyl, substitution benzenesulfonyl, methyl sulphonyl, substituent methyl sulfonyl, R3For hydrogen atom, benzene
Base, substituted-phenyl, alkyl, R4For hydrogen atom, phenyl, substituted-phenyl, alkyl,
The method of above-mentioned a kind of synthetic intermediate 16, which is characterized in that the highly basic is potassium hexamethyldisilazide, pregnancy
Two silicon substrate amido sodium of base, hexamethyldisilazide lithium, potassium tert-butoxide, lithium diisopropylamine, n-BuLi, tert-butyl lithium,
Potassium hydroxide, sodium hydroxide, the atent solvent are tetrahydrofuran, ether, 1,6- dioxane, methyl tertiary butyl ether(MTBE).
A method of synthesizing the intermediate 2, which is characterized in that synthesize in accordance with the following steps：
(1) compound 3 sloughs tertiary butyl, t-Butyldimethylsilyl and tertiary butyloxycarbonyl in atent solvent under strongly acidic conditions
These three protecting groups of base, obtained crude material is directly used in react in next step,
(2) acid amide condensation occurs under the conditions of crude product obtained in the previous step is existing for condensing agent and organic base in atent solvent
Annulation, obtain cyclic product 2,
Wherein, R in compound 3 and 21For 2 alkyl to 20 carbon.
The method of above-mentioned a kind of synthetic intermediate 2, which is characterized in that the strong acid is trifluoroacetic acid, pyrovinic acid, to methyl
Benzene sulfonic acid, trifluoromethane sulfonic acid.
The method of above-mentioned a kind of synthetic intermediate 2, which is characterized in that the atent solvent is dichloromethane, 1,2-, bis- chloroethenes
Alkane, chloroform, tetrahydrofuran, ether, 1,6- dioxane, methyl tertiary butyl ether(MTBE).
The method of above-mentioned a kind of synthetic intermediate 2, which is characterized in that the condensing agent is dicyclohexylcarbodiimide
(DCC), diisopropylcarbodiimide (DIC), 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (EDCI),
2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters (HATU), O- benzotriazole-tetramethyl
Urea hexafluorophosphate (HBTU), bis- (2- oxo -3- oxazolidinyls) secondary phosphoryl chloride phosphorus oxychlorides (BOP-Cl).
A kind of method of above-mentioned synthetic intermediate 2, which is characterized in that the organic base be triethylamine, diisopropylethylamine, 1,
11 carbon -7- alkene of 8- diazabicylos.
Description of the drawings
The general structure of Fig. 1 natural products BE-43547
The synthetic route of Fig. 2 compounds 5
The synthetic route of Fig. 3 compounds 16a
The synthetic route of Fig. 4 compounds BE-43547A2 (1a).
Specific implementation mode
In order to understand the present invention, further illustrated the present invention below with embodiment, but be not meant to the protection of the limitation present invention
Range.
Embodiment：The preparation of compound 1a
The synthetic route of compound 5 is shown in Fig. 2
In 250 mL round-bottomed flasks, under argon gas protection, compound S3 (10.27 g, 30.74 mmol) and two is sequentially added
50 mL of chloromethanes is stirred under setting to 0 degree Celsius.Compound S2 (6.54 g, 21.55 mmol) is dissolved in dichloromethane 20
ML is added dropwise to reaction system, continues stirring after twenty minutes, moves to room temperature reaction 2 hours.Reaction solution is concentrated, silica gel column chromatography
Purify to obtain compound S4 (14.75 g, 93%).1H NMR (400 MHz, CDCl3) δ 6.91(dd, J = 15.7, 5.2
Hz, 1H), 5.97(dd, J = 15.7, 1.7 Hz, 1H), 4.90(s, 1H), 4.35(s, 1H), 3.74(s,
3H), 3.75 – 3.68(m, 2H), 1.45(s, 9H), 0.88(s, 9H), 0.05(d, J = 3.6 Hz, 6H).
In 100 mL round-bottomed flasks, compound S4 (7.13 g, 19.83 mmol) and THF is sequentially added:H2O=3:1 mixing
100 mL of solution, is placed in and stirs at room temperature.One hydronium(ion) lithia (0.92 g, 21.81 mmol) is added into reaction system,
Continue to be stirred to react 20 h.By reaction solution rotate remove THF, be added dropwise into obtained solution 1 M aqueous hydrochloric acid solutions to pH value of solution=
3, aqueous solution is extracted with ethyl acetate (50 mL × 3), anhydrous sodium sulfate is added to the conical flask for the organic phase for filling merging
In, mixing is fully shaken, is filtered after standing and drying, filtrate is concentrated solution using Rotary Evaporators.Obtained crude product silica gel
Column purification, obtained product S5 are the grease (4.45 g, 65%) of colorless viscous.[α]20 D = - 1.1 (c = 1.0,
CHCl3); ν max (KBr): 3676, 3302, 3168, 2939, 2898, 2860, 1707, 1548, 1464, 1394,
1294, 1248, 1201, 1170, 1125, 844, 773, 667 cm-1; 1H NMR (400 MHz, CDCl3) δ
7.03 (dd, J = 15.7, 5.0 Hz, 1H), 6.00 (dd, J = 15.7, 1.7 Hz, 1H), 4.97 (s,
1H), 4.42 (s, 1H), 3.81 – 3.68 (m, 2H), 1.48 (s, 9H), 0.90 (s, 9H), 0.07 (d,J = 3.3 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 170.9, 155.4, 149.1, 121.5, 80.1,
64.7, 53.2, 28.5, 26.0, 18.4, -5.3, -5.4; HRMS (ESI) C16H30NO5Si- [M-H]-:It is theoretical
Value 344.1899, measured value 344.1896.
In 100 mL round-bottomed flasks, sequentially add compound S5 (4.22 g, 12.21 mmol), S6 (3.41 g, 24.43
Mmol) and 100 mL of dichloromethane, it is placed in and stirs 10 min at room temperature.By HOBt (19.80 g, 14.65 mmol), EDCI
(4.34 g, 24.43 mmol) and DIPEA (6.5 mL, 36.63 mmol) add to reaction system successively, continue to be stirred to react
Overnight.10 mL water to reaction systems are added, reaction is quenched, then respectively with 1% aqueous hydrochloric acid solution (50 mL), unsaturated carbonate hydrogen
Sodium (50 mL) and saturated salt solution (20 mL) are respectively washed once, and anhydrous sodium sulfate is added to the conical flask for filling organic phase
In, mixing is fully shaken, is filtered after standing and drying, filtrate is concentrated solution using Rotary Evaporators.Obtained crude product silica gel
Column purification, obtained product S7 are the grease (4.1 g, 78%) of colorless viscous.Rotamer ratio is about 4:1, NMR number
According to characterization major rotomer.[α]20 D = - 2.8 (c = 1.0, CHCl3); ν max (KBr): 3312, 2953,
2860, 1750, 1710, 1665, 1623, 1518, 1401, 1366, 1253, 1211, 1173, 1115, 841,
779 cm-1; 1H NMR (400 MHz, CDCl3) δ 6.83 (dd, J = 15.2, 5.6 Hz, 1H), 6.46 (d,J = 15.1 Hz, 1H), 4.91 (brs, 1H), 4.35 (brs, 1H), 4.18 (s, 2H), 3.77 – 3.68
(m, 2H), 3.73 (s, 3H), 3.14 (s, 3H), 1.45 (s, 9H) 0.88 (s, 9H), 0.06 (d, J =
2.6 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 169.8, 166.8, 155.4, 144.1, 120.8,
79.9, 64.8, 53.5, 52.3, 49.7, 36.8, 28.5, 26.0, 18.4, -5.3, -5.4; HRMS
(MALDI) C20H38N2O6SiNa+ [M + Na]+:Theoretical value 453.2391, measured value 453.2395.
In 100 mL round-bottomed flasks, compound S7 (3.90 g, 9.06 mmol) and THF is sequentially added:H2O=3:1 mixing
50 mL of solution, is placed in and stirs at room temperature.One hydronium(ion) lithia (0.49 g, 11.77 mmol) is added into reaction system, after
Continuous to be stirred to react 3 h, the reaction was complete for TLC detections.Reaction solution is rotated and removes THF, 1 M hydrochloric acid waters are added dropwise into obtained solution
Solution extracts aqueous solution to pH value of solution=2, with EtOAc (50 mL × 4), and anhydrous sodium sulfate is added to and fills the organic of merging
In the conical flask of phase, mixing is fully shaken, is filtered after standing and drying, filtrate is concentrated solution using Rotary Evaporators, silicagel column
Purify the grease (3.4 g, 90%) that obtained product 5 is colorless viscous.Rotamer ratio is about 2:1, NMR data table
Levy major rotomer.[α]20 D = + 7.3 (c = 1.0, CHCl3); ν max (KBr): 2936, 2861, 1711,
1664, 1613, 1498, 1403, 1367, 1252, 1171, 1115, 840, 779 cm-1; 1H NMR (400
MHz, MeOD) δ 6.81 – 6.70 (m, 1H), 6.59 (dd, J = 15.3, 1.7 Hz, 1H), 4.37 –
4.13 (m, 3H), 3.67 (d, J = 6.1 Hz, 1H), 3.18 (s, 3H), 1.46 (s, 9H), 0.91 (s,
9H), 0.09 (s, 6H); 13C NMR (100 MHz, CD3OD) δ 172.4, 168.9, 157.8, 145.1,
121.8, 80.4, 65.9, 55.2, 50.6, 37.2, 28.8, 26.4, 19.1, -5.3, -5.3; HRMS (ESI)
C19H35N2O6Si- [M-H]-:Theoretical value 415.2270, measured value 415.2268.
The synthetic route of compound 16a is shown in Fig. 3
Under argon gas protection, sequentially added to dichloromethane (150 mL) solution of compound 8 (22.0 g, 80.8 mmol)
Et3N (15.8 mL, 113 mmol) and TBSOTf (25.8 mL, 113 mmol) is stirred to react overnight at room temperature.
Rotary evaporation remove volatile reagent, to obtained residue in be added pentane (80 mL), stir 20 minutes.By upper layer
After pentane layer is slowly poured out, the crude product 9 that concentrated by rotary evaporation obtains is directly used in and reacts in next step.
Under argon gas protection, dichloromethane (150 mL) solution of aldehyde 10 (14.3 g, 67.3 mmol) is placed under -78 oC and is stirred
It mixes.The dichloromethane solution (74.0 mL, 74.0 mmol) of titanium tetrachloride is added into reaction solution.It, will be upper after stirring 30 minutes
The compound 9 that one step obtains is dissolved in dichloromethane (40 mL) and is added dropwise to reaction solution.Continue after being stirred to react 4 h, saturation is added
Aqueous ammonium chloride solution (50 mL) extracts reaction of going out.Reaction system is warmed to room temperature, liquid separation, the anhydrous sulphur of obtained organic phase are extracted
Sour sodium drying, concentration obtain crude Compound 11a, are directly used in and react in next step.
Under argon gas protection, alcohol 11a obtained in the previous step is dissolved in dichloromethane (225 mL) and is placed in and stirs at room temperature.To reaction
2,6-lutidin (67.3 mmol) and TBSOTf (67.3 mmol) are sequentially added in liquid, are stirred to react 1 h at room temperature.To
Methanol (5 mL) is added in reaction solution, reaction is quenched, by reaction solution with 5% NaHSO4Aqueous solution washs, obtained organic phase nothing
Aqueous sodium persulfate dry, concentrated after filtering, obtained crude product silica gel column purification, obtain colorless oil compound 12a (29.1 g,
Three-step reaction yield 60%).[α]20 D = - 22.6 (c = 1.0, CHCl3); ν max (KBr): 2927, 2855, 1697,
1463, 1382, 1333, 1260, 1210, 1165, 1130, 1058, 975, 945, 837, 776, 540 cm-1;1H NMR (400 MHz, CDCl3) δ 4.17 – 4.06 (m, 1H), 3.88 (dd, J = 7.7, 4.9 Hz, 1H),
3.48 (d, J = 13.8 Hz, 1H), 3.42 (d, J = 13.8 Hz, 1H), 3.35 – 3.22 (m, 1H),
2.10 – 1.82 (m, 5H), 1.45 – 1.33 (m, 4H), 1.29 – 1.19 (m, 22H), 1.14 (s, 3H),
1.11 (d, J = 6.7 Hz, 3H), 0.96 (s, 3H), 0.91 – 0.83 (m, 12H), 0.08 (d, J =
12.6 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 174.2, 72.7, 65.5, 53.3, 48.2, 47.9,
46.6, 44.9, 38.7, 33.0, 32.3, 32.1, 29.9, 29.8, 29.8, 29.7, 29.1, 26.6, 26.1,
25.0, 22.8, 21.0, 20.0, 18.3, 14.3, 10.4, -4.2, -4.9; HRMS (MALDI)
C33H63NO4SSiNa+ [M + Na]+:Theoretical value 620.4139, measured value 620.4145.
Under argon gas protection, compound 12a (29.4 g, 49.2 mmol) is dissolved in dichloromethane (160 mL) and is placed in -78 oC
Lower stirring.Into reaction solution be added DIBAL-H (36.0 mL, 54.0 mmol, 1.5 M toluene solutions), the reaction was continued 30 points
Clock.Methanol (10 mL) is added into reaction solution, reaction is quenched, after temperature of reaction system is warmed to room temperature, 2 N potassium tartrates are added
Sodium water solution (100 mL) continues stirring 30 minutes.Obtained reaction solution extracts (2 × 60 mL) with dichloromethane, merging
Organic phase is dried with anhydrous sodium sulfate, is concentrated after filtering, and obtained crude product obtains colorless oil compound 13a with silica gel column purification
(17.2 g, 90%)。
Under argon gas protection, dichloromethane (200 mL) solution of compound 8 (13.4 g, 49.2 mmol) is placed in -78 oC
Lower stirring.The dichloromethane solution (49.2 mL, 49.2 mmol) and DIPEA of 1 M titanium tetrachlorides are added into reaction solution
(8.10 mL, 49.2 mmol).It stirs after twenty minutes, by compound 13a obtained in the previous step (17.2 g, 44.7 mmol)
It is dissolved in dichloromethane (40 mL) and is added dropwise to reaction solution.Continue after being stirred to react 3 h, while triethylamine (60 mL) and water is added
(60 mL) extracts reaction of going out.Reaction system is warmed to room temperature, liquid separation is extracted, obtained organic phase is dried with anhydrous sodium sulfate, is filtered
After concentrate, obtain crude product silica gel column purification, obtain compound as white solid 7a (22.0 g, 75%). [α]20 D = -
60.7 (c = 1.0, CHCl3); ν max (KBr): 2928, 2856, 1677, 1462, 1388, 1330, 1246,
1165, 1126, 1065, 967, 836, 774, 535 cm-1; 1H NMR (400 MHz, CDCl3) δ 4.09 –
4.01 (m, 1H), 3.88 (t, J = 6.3 Hz, 1H), 3.72 (d, J = 10.3 Hz, 1H), 3.56 –
3.39 (m, 3H), 3.21 (q, J = 7.0 Hz, 1H), 2.11 – 2.00 (m, 2H), 1.98 – 1.83 (m,
3H), 1.83 – 1.71 (m, 1H), 1.48 – 1.32 (m, 4H), 1.25 (brs, 22H), 1.21 (d, J =
7.1 Hz, 3H), 1.16 (s, 3H), 0.98 (s, 3H), 0.93 – 0.84 (m, 12H), 0.80 (d, J =
6.9 Hz, 3H), 0.05 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 178.0, 72.2, 72.1, 65.1,
53.2, 48.5, 47.9, 44.8, 41.2, 40.9, 38.5, 33.0, 32.1, 30.6, 30.0, 29.9, 29.8,
29.8, 29.5, 26.8, 26.6, 26.1, 22.9, 21.0, 20.0, 18.3, 14.3, 10.3, 9.6, -4.2,
-4.4; HRMS (MALDI) C36H69NO5SSiNa+ [M + Na]+:Theoretical value 678.4558, measured value 678.4562.
In 500 mL round-bottomed flasks, compound 7a (4.00 g, 6.09 mmol) and THF is sequentially added:H2O=3:1 mixing
Solution (150 mL), is placed in and stirs at room temperature.One hydronium(ion) lithia (1.54 g, 36.6 mmol) is added into reaction system,
Continue to be stirred to react 7 h.By reaction solution rotate remove THF, be added dropwise into obtained solution 1 N aqueous hydrochloric acid solutions to pH value of solution=
1, aqueous solution is extracted with EtOAc (80 mL × 4), anhydrous sodium sulfate is added in the conical flask for the organic phase for filling merging,
Mixing is fully shaken, is filtered after standing and drying, is concentrated, obtained crude product is directly used in react in next step.
In 100 mL round-bottomed flasks, sequentially add crude Compound obtained in the previous step, tert-butyl glycinate 14 (1.20 g,
9.14 mmol) and 35 mL of dichloromethane.By HOBt (0.98 g, 7.31 mmol), and EDCI (1.40 g, 7.31
Mmol) and DIPEA (1.20 mL, 7.31 mmol) adds to reaction system successively, continues to be stirred to react 3 h.10 mL water are added
Reaction is quenched to reaction system, then with after 50 mL dichloromethane dilute reaction solutions, respectively with 1% aqueous hydrochloric acid solution (30
ML), saturated sodium bicarbonate (30 mL) and saturated salt solution (30 mL) are respectively washed once, and anhydrous sodium sulfate is added to and has been filled
In the conical flask of machine phase, mixing is fully shaken, is filtered after standing and drying, concentrated.Obtained crude product silica gel column purification, obtains
Product 15a is colorless oil (2.30 g, two step yields 70%).[α]20 D = - 1.1 (c = 1.0, CHCl3); ν max
(KBr): 2928, 2856, 1741, 1647, 1544, 1463, 1372, 1309, 1250, 1161, 1070, 972,
837, 775 cm-1; 1H NMR (400 MHz, CDCl3) δ 6.78 (t, J = 5.1 Hz, 1H), 4.12 (s,
1H), 4.03 – 3.81 (m, 3H), 3.74 (d, J = 9.8 Hz, 1H), 2.46 (q, J = 7.2 Hz, 1H),
1.83 – 1.72 (m, 1H), 1.46 (s, 9H), 1.43 – 1.34 (m, 2H), 1.24 (brs, 22H), 1.17
(d, J = 7.2 Hz, 3H), 0.96 – 0.81 (m, 12H), 0.76 (d, J = 6.9 Hz, 3H), 0.07 (d,J = 3.3 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 177.2, 169.2, 82.4, 74.9, 73.7,
42.5, 42.1, 40.5, 32.8, 32.1, 30.0, 29.9, 29.8, 29.5, 28.2, 26.1, 25.6, 22.8,
18.2, 14.3, 11.7, 10.1, -4.3, -4.3; HRMS (MALDI) C32H65NO5SiNa+ [M + Na]+:Reason
By value 594.4524, measured value 594.4528.
In 100 mL round-bottomed flasks, compound 15a (1.96 g, 3.42 mmol) and 30 ml dichloromethane are sequentially added, in
It stirs at room temperature.Dess-Martin reagents (2.18 g, 5.13 mmol) are added to reaction system.Reaction system is in room temperature
Stir 1 h.10 mL saturations Na is added into reaction solution2S2O3It is saturated NaHCO with 10 mL3Reaction is quenched in aqueous solution.Extraction point
Liquid, water phase extract (4 × 30 mL) with dichloromethane, and combined organic phase is dried with anhydrous sodium sulfate, concentration.What is obtained is thick
Product silica gel column purification obtains colorless oil compound 6a (1.82 g, 93%).Isomer proportion is 2:1, NMR data characterization
Main isomer.ν max (KBr): 3303, 2927, 2856, 1745, 1653, 1536, 1462, 1368, 1297,
1225, 1159, 1078, 1010, 945, 777, 725, 669, 592, 511 cm-1; 1H NMR (400 MHz,
CDCl3) δ 6.63 (brs, 1H), 4.03 – 3.79 (m, 3H), 3.65 – 3.53 (m, 1H), 2.97 (p, J
= 6.8 Hz, 1H), 1.50 – 1.34 (m, 2H), 1.47 (s, 9H), 1.35 (d, J = 6.9 Hz, 3H),
1.25 (s, 22H), 0.98 (d, J = 6.7 Hz, 3H), 0.90 – 0.82 (m, 12H), 0.06 (d, J =
6.6 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 211.3, 170.4, 168.7, 82.4, 74.0, 55.0,
50.6, 42.3, 33.7, 32.1, 30.1, 29.8, 29.8, 29.8, 29.5, 28.2, 26.0, 26.0, 23.2,
22.8, 18.2, 14.7, 14.3, 13.1, -4.4, -4.6; HRMS (MALDI) C32H63NO5SiNa+ [M + Na]+
:Theoretical value 592.4373, measured value 592.4372.
Under argon gas protection, compound 6a (1.69 g, 2.96 mmol) dry THFs (24 mL) dissolve, in -78 C low temperature
Lower stirring.KHMDS (THF solution of 1 M, 3.11 mL, 3.11 mmol) is added dropwise in reaction solution, stirring 20 is continued
min.D-CSO (680 mg, 2.96 mmol) is dissolved in the anhydrous THF of 5 mL, reaction system is added dropwise to.It is added dropwise,
The reaction was continued 6 h.5 mL saturated aqueous ammonium chlorides are added to reaction solution, reaction is quenched, is warmed to room temperature, and reaction solution is used
Rotary Evaporators concentrate solution, 20 mL water of residue and the dilution of 50 mL ethyl acetate, liquid separation.Water phase ethyl acetate (3
× 30 mL) it extracts three times, combined organic phase is dried with anhydrous sodium sulfate, is concentrated after filtering, and silica gel column chromatography purifying obtains nothing
Color oily compound 16a (1.46 g, 84%).[α]20 D = + 42.8 (c = 1.0, CHCl3);ν max (KBr): 3408,
2926, 2856, 2737, 1742, 1680, 1519, 1462, 1367, 1251, 1160, 1007, 944, 778,
722, 668, 599, 507 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.44 (t, J = 5.4 Hz, 1H),
5.12 (s, 1H), 4.00 – 3.84 (m, 3H), 3.66 – 3.53 (m, 1H), 1.63 – 1.57 (m, 1H),
1.52 (s, 3H), 1.55 – 1.49 (m, 1H), 1.47 (s, 9H), 1.26 (s, 22H), 0.98 (d, J =
6.8 Hz, 3H), 0.88 (t, J = 6.8 Hz, 3H), 0.85 (s, 9H), 0.04 (d, J = 23.4 Hz,
6H); 13C NMR (100 MHz, CDCl3) δ 211.1, 171.1, 168.4, 82.4, 81.6, 74.3, 45.2,
42.2, 33.2, 32.1, 30.1, 29.9, 29.8, 29.8, 29.5, 28.2, 26.0, 24.4, 23.0, 22.8,
18.2, 14.3, 13.8, -4.4, -4.7; HRMS (MALDI) C32H63NO6SiNa+ [M + Na]+:Theoretical value
608.4317 measured value 608.4320.
The synthetic route of compound 1a is shown in Fig. 4
In 250 mL round-bottomed flasks, compound 16a (8.80 g, 15.0 mmol) is dissolved in THF (60 mL), is added
TBAF (18.4 mL, 18.4 mmol, 1 M THF solutions), continues to be stirred to react 2 h.Saturated aqueous ammonium chloride is added
Reaction is quenched in (30 mL), then with 120 mL ethyl acetate and 40 mL water dilute reaction solutions, water phase with ethyl acetate (3 ×
80 mL) extraction.Combined organic phase is dried with anhydrous sodium sulfate, is concentrated after filtering.Obtained crude product silica gel column purification, obtains
To compound 4a (7.20 g, 99%). [α]20 D = - 35.5 (c = 0.6, CHCl3); ν max (KBr): 3537,
3412, 3323, 2922, 2852, 1736, 1714, 1660, 1525, 1462, 1449, 1367, 1240, 1163,
1123, 942, 904, 847, 751, 715, 618 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.40 (t, J
= 5.5 Hz, 1H), 4.97 (s, 1H), 3.90 (dd, J = 18.0, 5.3 Hz, 1H), 3.83 (dd, J =
18.0, 5.6 Hz, 1H), 3.65 – 3.53 (m, 2H), 2.56 (brs, 1H), 1.77 – 1.63 (m, 1H),
1.58 (s, 3H), 1.62 – 1.53 (m, 1H), 1.46 (s, 9H), 1.25 (brs, 22H), 1.08 (d, J
= 6.4 Hz, 3H), 0.87 (t, J = 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 213.1,
171.1, 168.6, 82.7, 82.3, 75.1, 45.9, 42.3, 35.0, 32.1, 29.8, 29.8, 29.8,
29.8, 29.7, 29.5, 28.2, 25.1, 24.0, 22.8, 15.4, 14.3; HRMS (MALDI) C26H49NO6Na+
[M + Na]+:Theoretical value 494.3452, measured value 494.3458.
In 50 mL round-bottomed flasks, be added compound 4a (396 mg, 0.83 mmol) and compound 5 (520 mg, 1.25
Mmol), it is used in combination 10 mL dichloromethane to dissolve, is stirred in 0 oC.By DMAP (20 mg, 0.17 mmol) and DIC (260 μ L,
1.66 mmol) it adds in reaction flask successively, reaction system continues to stir 40 min in room temperature.Then slowly add to reaction solution
Enter 1 mL water quenchings to go out reaction, then concentrate reaction solution, residue is diluted with 1% aqueous hydrochloric acid solution of 10 mL ether and 5 mL
Afterwards, liquid separation.Organic phase is washed once with saturated sodium bicarbonate (5 mL), anhydrous sodium sulfate drying, and filtering will using Rotary Evaporators
Solution concentrates, and silica gel column chromatography purifying obtains colorless oil compound 3a (510 mg, 70%).Rotamer ratio is about 4:
1, NMR data characterizes major rotomer. [α]20 D = - 6.6 (c = 1.0, CHCl3); ν max (KBr): 3334,
2926, 2856, 1742, 1673, 1621, 1516, 1464, 1368, 1251, 1166, 1014, 975, 841,
781, 669, 586, 509 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.50 (t, J = 5.6 Hz, 1H),
6.78 (dd, J = 15.1, 5.9 Hz, 1H), 6.41 (d, J = 15.1 Hz, 1H), 5.32 (s, 1H),
5.21 – 5.10 (m, 1H), 4.95 – 4.88 (m, 1H), 4.39 – 4.25 (m, 1H), 4.10 – 3.56
(m, 6H), 3.11 (s, 3H), 1.68 – 1.57 (m, 1H), 1.54 (s, 3H), 1.51 – 1.35 (m,
19H), 1.23 (brs, 22H), 1.03 (d, J = 7.0 Hz, 3H), 0.92 – 0.81 (m, 12H), 0.04
(d, J = 2.7 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 210.1, 171.1, 168.4, 168.1,
167.0, 155.4, 144.5, 120.7, 82.3, 81.2, 76.4, 64.8, 50.0, 43.7, 42.1, 37.0,
32.0, 31.5, 29.8, 29.8, 29.8, 29.7, 29.6, 29.6, 29.5, 28.5, 28.1, 26.0, 24.8,
23.6, 22.8, 18.4, 15.2, 14.2, -5.3, -5.4; HRMS (MALDI) C45H83N3O11SiNa+ [M + Na
]+:Theoretical value 892.5689, measured value 892.5695.
In 10 mL round-bottomed flasks, compound 3a (420 mg, 0.48 mmol) is added and is dissolved with 5 mL dichloromethane, in 0
It is stirred under C.Trifluoroacetic acid (3.3 mL) is added into reaction system, reaction system continues after stirring 30 min, and it is anti-to be transferred to room temperature
Answer 6 h.5 mL dilution with toluene reaction solutions are added to reaction solution, then reaction solution is rotated and removes organic solvent, obtained residue
For white solid, not purified be directly used in is reacted in next step.
In 1000 mL round-bottomed flasks, HATU (2.76 g, 7.23 mmol) and the anhydrous THF of 500 mL is added, stirs at room temperature
It mixes, then DIPEA (2.4 mL, 14.46 mmol) is added.It is anhydrous that white solid obtained in the previous step is dissolved in 20 mL
In THF, solution is added slowly in reaction solution using syringe pump, the process of dropwise addition is more than 12 h.It is added dropwise, continues to stir 2 h
Afterwards, reaction solution is spin-dried for, obtains brown color residue.By 250 mL ethyl acetate of residue:Methanol=2:1 mixed solvent dissolving,
Diatomite filters, and after filtrate is concentrated solution using Rotary Evaporators, is dissolved in 250 mL ethyl acetate.Then respectively with 1%
Aqueous hydrochloric acid solution (60 mL), saturated sodium bicarbonate aqueous solution and full (60 mL) and saline solution (60 mL) wash.Organic phase is used
Anhydrous sodium sulfate is dried, and is filtered, concentration, silica gel column chromatography purifying, obtains compound as white solid 2a (132 mg, the production of two steps
Rate 47%). [α]20 D = + 38.9 (c = 0.35, CHCl3); ν max (KBr): 3638, 3352, 2953, 2921,
2856, 2725, 1753, 1660, 1555, 1459, 1373, 1262, 1190, 1095, 1027, 850, 805,
687, 561 cm-1; 1H NMR (400 MHz, DMSO-d 6 ) δ 8.69 (t, J = 5.9 Hz, 1H), 7.41 (d,J = 9.3 Hz, 1H), 6.79 (s, 1H), 6.73 (dd, J = 15.1, 3.4 Hz, 1H), 6.16 (dd, J =
15.1, 2.0 Hz, 1H), 5.02 (t, J = 5.6 Hz, 1H), 4.92 (td, J = 9.3, 2.6 Hz, 1H),
4.64 – 4.56 (m, 1H), 4.58 (d, J = 19.1 Hz, 1H), 4.02 (d, J = 19.4 Hz, 1H),
3.76 (dd, J = 16.8, 5.6 Hz, 1H), 3.63 (dd, J = 16.8, 6.2 Hz, 1H), 3.53 – 3.40
(m, 2H), 3.38 – 3.32 (m, 1H),2.82 (s, 3H), 1.72 – 1.65 (m, 1H), 1.62 (s, 3H),
1.57 – 1.47 (m, 1H), 1.23 (brs, 22H), 1.10 (d, J = 6.7 Hz, 3H), 0.85 (t, J =
6.5 Hz, 3H); 13C NMR (100 MHz, DMSO-d 6) δ 212.4, 173.5, 168.8, 167.8, 166.9,
142.9, 119.3, 80.0, 76.9, 63.0, 51.8, 50.1, 43.3, 43.1, 34.9, 31.3, 29.1,
29.1, 29.0, 29.0, 28.8, 28.7, 24.4, 22.1, 21.1, 15.8, 14.0; HRMS (MALDI) c
C30H51N3O8Na+ [M + Na]+:Theoretical value 604.3568, measured value 604.3570.
In 100 mL round-bottomed flasks, compound 2a (630 mg, 1.08 mmol) is added and is dissolved with the anhydrous THF of 28 mL, in 0
It is stirred under C.(300 μ L, 2.16 mmol) and MsCl (130 μ L, 1.62 mmol) are added into reaction system successively, are reacted
System continues after stirring 30 min.200 μ L water are added to reaction solution, are concentrated solution using Rotary Evaporators, residue is used
EtOAc (80 mL) dissolves, and anhydrous sodium sulfate drying is concentrated to give residue, and not purified be directly used in is reacted in next step.
In 50 mL round-bottomed flasks, white solid obtained in the previous step is added and is dissolved in the anhydrous THF of 20 mL, and stirs at room temperature
It mixes.Then DBU (650 μ L, 4.32 mmol) is added, continues to be stirred to react 1 h.Then it after ethyl acetate dilution is added, uses
1% sodium bisulphate solution (100 mL), saturated sodium bicarbonate aqueous solution (50 mL) and saturated salt solution (50 mL) respectively wash one
Secondary, solution is concentrated into the concentrate of substantially 30 mL using Rotary Evaporators, by concentrate silicon by anhydrous sodium sulfate drying
Rubber column gel column purifies, and solution is concentrated into the concentrate of substantially 30 mL using Rotary Evaporators by obtained solution, and 20 uncles mL are added
Butanol dilutes, and is continuing with the concentrate that solution is concentrated into substantially 20 mL by Rotary Evaporators, is dried with freeze drier,
Obtain powdered compounds 1a (350 mg, two step yields 57%).[α]20 D = + 14.1 (c = 0.25, CHCl3 :
MeOH = 1 : 1); ν max (KBr): 2924, 2852, 2361, 1747, 1658, 1591, 1527, 1465,
1262, 1193, 1102, 1023, 805, 670 cm-1; 1H NMR (400 MHz, DMSO-d 6 ) δ8.79 (t, J =
6.1 Hz, 1H), 8.69 (s, 1H), 6.98 (d, J = 15.2 Hz, 1H), 6.73 (s, 1H), 6.34 (d,J = 15.2 Hz, 1H), 5.77 (s, 1H), 5.40 (s, 1H), 5.02 – 4.90 (m, 1H), 4.41 (d, J
= 19.2 Hz, 1H), 4.15 (d, J = 19.3 Hz, 1H), 3.96 (dd, J = 16.3, 5.6 Hz, 1H),
3.69 (dd, J = 16.2, 6.5 Hz, 1H), 3.47 – 3.36 (m, 1H), 2.87 (s, 3H), 1.73 –
1.64 (m, 1H), 1.60 (s, 3H), 1.58 – 1.44 (m, 1H), 1.23 (brs, 22H), 1.08 (d, J
= 6.8 Hz, 3H), 0.85 (t, J = 6.6 Hz, 3H); 13C NMR (100 MHz, DMSO-d 6) δ 212.0,
173.8, 168.8, 167.7, 166.4, 139.4, 137.3, 116.8, 114.2, 80.7, 76.5, 50.2,
44.3, 43.5, 35.0, 31.3, 31.1, 29.0, 29.0, 28.9, 28.7, 24.5, 22.1, 20.9, 15.7,
14.0; HRMS (MALDI) C30H49N3O7Na+ [M + Na]+:Theoretical value 586.3463, measured value 586.3468.
Claims (13)
1. a kind of preparation method of 1 compound of formula,
Wherein, the R of compound 11,12,13,7,15,6,16,4,3,2,11For 2 alkyl to 20 carbon.
2. according to claim 1, a kind of intermediate 6 for synthesizing 1 compound of formula,
Wherein, R in compound 61For 2 alkyl to 20 carbon.
3. according to claim 1, a kind of intermediate 16 for synthesizing 1 compound of formula,
Wherein, R in compound 161For 2 alkyl to 20 carbon.
4. according to claim 1, a kind of intermediate 3 for synthesizing 1 compound of formula,
Wherein, R in compound 31For 2 alkyl to 20 carbon.
5. according to claim 1, a kind of intermediate 2 for synthesizing 1 compound of formula,
Wherein, R in compound 31For 2 alkyl to 20 carbon.
6. according to claim 3, a method of the intermediate 16 described in synthesis claim 3, which is characterized in that the change of highly basic
Object 6 and nitrogen oxa- ternary cyclics (II) are closed, reaction generates compound 16, highly basic in atent solvent under basic conditions
Molar equivalent ratio with compound 6 is 0.2: 1 ~ 1.1 :1,
Wherein, R in compound 6 and 161For 2 alkyl to 20 carbon.
7. according to claim 6, a kind of method of synthetic intermediate 16, which is characterized in that nitrogen oxa- three-membered ring class
Object (II) is closed as shown, R wherein in formula (II)2For benzenesulfonyl, substitution benzenesulfonyl, methyl sulphonyl, substituent methyl sulphur
Acyl group, R3For hydrogen atom, phenyl, substituted-phenyl, alkyl, R4For hydrogen atom, phenyl, substituted-phenyl, alkyl,
。
8. according to claim 6, the method for a kind of synthetic intermediate 16, which is characterized in that the highly basic is hexamethyl
Two silicon substrate amido potassium, sodium hexamethyldisilazide, hexamethyldisilazide lithium, potassium tert-butoxide, lithium diisopropylamine, just
Butyl lithium, tert-butyl lithium, potassium hydroxide, sodium hydroxide, the atent solvent are tetrahydrofuran, ether, 1,6- dioxane, first
Base tertbutyl ether.
9. according to claim 5, a method of synthesizing the intermediate 2, which is characterized in that synthesize in accordance with the following steps：
(1) compound 3 sloughs tertiary butyl, t-Butyldimethylsilyl and tertiary butyloxycarbonyl in atent solvent under strongly acidic conditions
These three protecting groups of base, obtained crude material is directly used in react in next step,
(2) acid amide condensation occurs under the conditions of crude product obtained in the previous step is existing for condensing agent and organic base in atent solvent
Annulation, obtain cyclic product 2,
Wherein, R in compound 3 and 21For 2 alkyl to 20 carbon.
10. according to claim 9, the method for a kind of synthetic intermediate 2, which is characterized in that the strong acid is trifluoro second
Acid, pyrovinic acid, p-methyl benzenesulfonic acid, trifluoromethane sulfonic acid.
11. according to claim 9, the method for a kind of synthetic intermediate 2, which is characterized in that the atent solvent is two
Chloromethanes, 1,2- dichloroethanes, chloroform, tetrahydrofuran, ether, 1,6- dioxane, methyl tertiary butyl ether(MTBE).
12. according to claim 9, the method for a kind of synthetic intermediate 2, which is characterized in that the condensing agent is two rings
Hexyl carbodiimide (DCC), diisopropylcarbodiimide (DIC), 1- (3- dimethylamino-propyls) -3- ethyl carbodiimide salt
Hydrochlorate (EDCI), 2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters (HATU), O- benzos three
Nitrogen azoles-tetramethylurea hexafluorophosphate (HBTU), bis- (2- oxo -3- oxazolidinyls) secondary phosphoryl chloride phosphorus oxychlorides (BOP-Cl).
13. according to claim 9, the method for a kind of synthetic intermediate 2, which is characterized in that the organic base is three second
Amine, diisopropylethylamine, 11 carbon -7- alkene of 1,8- diazabicylos.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111825631A (en) * | 2019-04-13 | 2020-10-27 | 南开大学 | BE-43547 derivative and its salt, preparation method and use in preparing anticancer medicine |
| CN114957390A (en) * | 2022-05-10 | 2022-08-30 | 苏州大学 | Tumor targeting polypeptide and application thereof |
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| JPH10147594A (en) * | 1996-11-19 | 1998-06-02 | Banyu Pharmaceut Co Ltd | Antitumor substances be-43547s |
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2017
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JPH10147594A (en) * | 1996-11-19 | 1998-06-02 | Banyu Pharmaceut Co Ltd | Antitumor substances be-43547s |
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| AMANDA L WATERS等: "An analysis of the sponge Acanthostrongylophora igens" microbiome yields an actinomycete that produces the natural product manzamine A", 《FRONT MAR SCI》 * |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111825631A (en) * | 2019-04-13 | 2020-10-27 | 南开大学 | BE-43547 derivative and its salt, preparation method and use in preparing anticancer medicine |
| CN111825631B (en) * | 2019-04-13 | 2023-10-13 | 新沂尚德药缘药业有限公司 | BE-43547 derivative and salt thereof, preparation method and application thereof in preparation of anticancer drugs |
| CN114957390A (en) * | 2022-05-10 | 2022-08-30 | 苏州大学 | Tumor targeting polypeptide and application thereof |
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