CN105566412A - Preparation method of etoposide, teniposide and analogs of etoposide and teniposide - Google Patents

Preparation method of etoposide, teniposide and analogs of etoposide and teniposide Download PDF

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CN105566412A
CN105566412A CN201610029133.0A CN201610029133A CN105566412A CN 105566412 A CN105566412 A CN 105566412A CN 201610029133 A CN201610029133 A CN 201610029133A CN 105566412 A CN105566412 A CN 105566412A
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full guard
base
epipodophyllotoxin
preparation
teniposide
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孙建松
刘慧�
廖进喜
涂媛鸿
熊斌
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Jiangxi Normal University
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    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
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    • Y02P20/00—Technologies relating to chemical industry
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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention discloses a preparation method of etoposide, teniposide and analogs of etoposide and teniposide. The preparation method includes the following steps of 1, selective protection of 4'domethylpodophyllotoxin4'hydroxy; 2, introduction of 4 hydroxy hydroxyl; 3, removal of a protecting group. The method is mild in reaction condition and environmentally friendly, and the yield and purity of the products are high.

Description

The preparation method of a kind of Etoposide and teniposide and analogue thereof
Technical field
The present invention relates to the preparation method of a kind of Etoposide and teniposide and analogue thereof.
Background technology
Lignin compound is extensively present among vegetable kingdom, as the oxidative dimerization of secondary metabolism source of product in Phenylpropanoid Glycosides. [1]up to the present be separated from the root of the plant of 17 sections, stem, leaf, seed and fruit and obtained lignin compound.Although only containing two C in the molecular structure of chemically this compounds of structural point 6-C 3phenylpropanoid Glycosides unit, but this compounds shows complex structure and diversity by the mode of connection of change two Phenylpropanoid Glycosides unit.
Biological activity test display Lignanoids compounds has extraordinary medical active, mainly comprises antitumor, anti-infective, immunosuppression, cardiovascular and cerebrovascular protection, anti-oxidant and antiviral etc.Lignin compound the most famous surely belongs to podophyllotoxin, and podophyllotoxin belongs to aryl-tetralin class xylogen, has been proved to be and has had good antimitotic activity.Early studies in man finds that podophyllotoxin is really very efficient to the treatment of tumour, but regrettably its toxic side effect is too large, thus limits it and use as antitumor drug.Podophyllotoxin not only increases required activity after carrying out glycosylation deriving, and toxic side effect also reduces greatly.Therefore, the treatment of the clinical treatment, particularly small cell lung cancer of tumour has been widely used in as the inhibitor of DNA topoisomerase II.
Botta, B.; DelleMonache, G.; Misiti, D.; Vitali, A.; Zappia, G.Curr.Med.Chem.2001,8,1363, thus have and good use prospect.And podophyllotoxin 4-OH glycosylation is the difficult point in carbohydrate chemistry field, mainly because this hydroxyl is in the benzyl position of electron rich phenyl ring, easily leaves away at acidic conditions and generates benzylic cation.And the Lewis acid that the glycosylation condition of nearly all routine is all equivalent or catalytic amount is carried out under promoting, thus while activation is to body, acceptor is also activated thus causes reaction yield on the low side.Several chemists are only had to complete synthesis (a) Helv.Chim.Acta1968 of Podophyllotoxin and its derivatives 5-O-glucosides, 51,163.Helv.Chim.Acta1968 at present, 51,1631. (b) TetrahedronLett.1991,32,1653 (c) TetrahedronLett.1992,33,4831. (d) J.Org.Chem.1993,58,4175. (e) Eur.J.Med.Chem.2012,47,424..But this several method all has the shortcomings such as productive rate is low, and configuration is wayward, and toxicity is larger.
Summary of the invention
The object of the present invention is to provide the preparation method of a kind of Etoposide and teniposide and analogue thereof, the method mild condition, environmental protection, the productive rate of product and purity are all higher.The method comprises the steps (2) ~ (3) or step (1) ~ (3).
The selective protection of 4 ' position hydroxyl of (1) 4 ' demethyl epipodophyllotoxin; The epipodophyllotoxin analog derivative of (2) 4 ' position hydroxyl protections and 4 hydroxyls of podophyllotoxin acceptor occur glycosylation; (3) the removing of protecting group.
Specifically, recommend each step as follows:
(1) with 4 ' demethyl epipodophyllotoxin for raw material, introduce R 1optionally protect 4 ' position hydroxyl, obtain the epipodophyllotoxin analog derivative 3 of 4 ' position hydroxyl protection.
Wherein, R 1for the hydroxyl protecting group that this area is conventional, described protecting group is preferably benzyl, t-Butyldimethylsilyl, methyl;
The epipodophyllotoxin analog derivative of (2) 4 ' position hydroxyl protections and 4 hydroxyls of podophyllotoxin acceptor occur glycosylation, and 4 that obtain full guard connect glycosyl R 2epipodophyllotoxin and podophillotoxines glucosides 2.
Wherein R 2for the β-D-Glucose base of full guard, the alpha-D-glucose base of full guard, β-D-the galactosyl of full guard, α-D-the galactosyl of full guard, β-D-MANNOSE the base of full guard, α-D-MANNOSE the base of full guard, β-D-the xylosyl of full guard, the alpha-D-xylose base of full guard, β-D-2-aminoglucose the glycosyl of full guard, α-D-2-aminoglucose the glycosyl of full guard, α-L-the rhamanopyranosyl of full guard, β-L-the rhamanopyranosyl of full guard, α-D-ribose the base of full guard, β-D-ribose the base of full guard, α-L-the ribosyl of full guard, β-L-the ribosyl of full guard, α-D-R the base of full guard, β-D-R the base of full guard, α-L-arabinose the base of full guard, β-L-arabinose the base of full guard, α-L-fucose the base of full guard, β-L-fucose the base of full guard, β-D-Glucose aldehydic acid the base of full guard, the alpha-D-glucose aldehydic acid base of full guard, β-D-galacturonic the acidic group of full guard, or the α-D-galacturonic acidic group of full guard, protecting group wherein on sugar is ethanoyl, benzoyl, benzyl, acetaldehyde fork, and thiophene aldehyde fork, AZMB structural formula are deng,
The epipodophyllotoxin of (3) 4 ' position hydroxyl protections and podophyllotoxin derivative glucosides 2 deprotection base obtain Etoposide and teniposide and analogue 1 thereof.
Described step (1) 4 ' demethyl epipodophyllotoxin 4 ' position hydroxyl protecting group R 1introducing in, 4 ' demethyl epipodophyllotoxin with containing the reactant R of protecting group 1the mol ratio of X is 1:1.0-1.5, and temperature of reaction is-10-25 DEG C, and the reaction times is 0.54-12 hour, the organic solvent of reaction is selected from haloalkane, triethylamine, pyridine, the N of C1-C4, at least one in dinethylformamide, react and carry out under the effect of alkali, X is selected from halogen; The mol ratio 1:1.0-1.5 of epipodophyllotoxin and alkali;
In the described epipodophyllotoxin analog derivative of step (2) 4 ' position hydroxyl protection and 4 hydroxyl glycosylation reactions of podophyllotoxin acceptor; 4 secondary hydroxyl acceptors and glycosyl alkynes ester to body 4 in organic solvent with under protection of inert gas; glycosylation reaction is there is under Lewis acid effect
Described glycosyl alkynes ester to body is (4), R 3be selected from the alkyl of C1-C6, C3-C10 cycloalkyl or aryl;
The epipodophyllotoxin analog derivative acceptor (3) of 4 ' described position hydroxyl protection and podophyllotoxin acceptor, glycosyl alkynes ester are 1:21.05-53.0:0.051-0.05 to body (4), lewis acidic mol ratio, temperature of reaction is room temperature, reaction times is 0.5-12 hour, and the organic solvent of reaction is selected from least one in toluene, methylene dichloride, ether and acetonitrile;
Described step (1) alkali is selected from pyridine, triethylamine, DMAP, ethamine, imidazoles, sodium hydride, potassium hydride KH, lithium diisopropylamine or lithium hexamethyldisilazide; The Lewis acid of described step (3) is Au catalyst or molecular sieve, and Au catalyst is AuCl, AuCl 3, PPh 3auOTf or PPh 3auNTf 2, OTf is trifyl, NTf 2be that two trifyls are amino; Molecular sieve is molecular sieve or pickling molecular sieve, the mass ratio of substrate and molecular sieve is 1:2-10, and rare gas element is high-purity nitrogen, argon gas or helium.
Described R 2for
Wherein Bz is benzoyl, and TBDPS is that the phenylbenzene tertiary butyl is silica-based, and AZMB is r described in 55 3for or
Technique effect of the present invention is: preparation method of the present invention is a kind of efficient, easy handling, environmental protection, synthesis Etoposide applied widely, the chemical process of teniposide and analogue thereof.And the method, when introducing 4 glycosyls of Etoposide and teniposide and analogue, has good regioselectivity, is incorporated into 4 by glycosyl selectivity, occur without 4 chiral photo-isomerisation side reactions.Therefore the discovery of preparation method of the present invention will be conducive to the exploitation of this compounds.
Embodiment
The following detailed description of the beneficial effect that the present invention has, be intended to help reader to understand essence of the present invention better, but any restriction can not be formed to enforcement of the present invention and protection domain.
The room temperature related in following each embodiment is 20 ~ 35 DEG C.
Embodiment 1
The preparation of podophyllotoxin 4-O-(2,3,4,6-tetra--O-benzoyl-β-D-Glucose) podophyllotoxin glucosides
Step 1: the glucose of full benzoyl protection is to the synthesis of body:
Under nitrogen protection; by the glucose 5g of full Bz protection exposed for different head position; 8.4mmol and adjacent alkynyl phenylformic acid 1.87g, 10.1mmol are dissolved in dry 10mLDCM, then in system, add EDCI2g; 10.1mmol; DMAP1g, 10mmol and DIPEA3ml, 16.7mmol; and track to reaction end in stirred at ambient temperature 3h, TLC.By thick for reaction system concentrating under reduced pressure product, then column chromatography obtains glucose alkynes ester to body (6.1g, 95%);
Step 2: the preparation of podophyllotoxin 4-O-(2,3,4,6-tetra--O-benzoyl-β-D-Glucose) podophyllotoxin glucosides
Under nitrogen protection, the glucose protected by full benzoyl is dissolved in dry 3mLDCM to body 115mg, 0.15mmol and podophyllotoxin 41mg, 0.1mmol, after reaction system at room temperature stirs 30min, adds Ph 3pAuNTf 222mg, 0.03mmol, stirring at room temperature is until react completely.Obtain thick product after reaction system concentrating under reduced pressure, column chromatography purification obtains target product 82.4mg, and 83%
[α] 26 D＝-0.366(c＝0.76inCHCl 3)； 1HNMR(400MHz,CDCl 3):δ7.94(t,J＝7.2Hz,4H),7.87(d,J＝7.2Hz,2H),7.82(d,J＝7.2Hz,2H),7.52(m,12H),7.12(s,1H),6.48(s,1H),6.33(s,2H),5.96(m,3H),5.70(m,2H),5.00(dd,J＝3.2,7.6Hz,2H),4.70(dd,J＝2.4,12.4Hz,1H),4.54(m,3H),4.20(m,1H),4.09(t,J＝9.6Hz,1H),3.73(s,6H),3.67(s,3H),2.91(m,1H),2.75(dd,J＝4.4,14.4Hz)； 13CNMR(400MHzCDCl 3)δ173.7,166.0,165.8,165.1,164.9,162.6,148.1,147.6,133.6，129.8,129.7,129.1,128.6,128.5,128.3,109.5,108.6,108.0,101.4,99.0,88.0,77.3,77.2,71.8,71.1,69.6,62.9,60.6,56.4,45.5,43.9,38.5.HRMS(m/z):[M+Na] +calcdforC56H48Na +O171015.2784,found1015.2787。
Embodiment 2
The preparation of epipodophyllotoxin 4-O-(2,3,4,6-tetra--O-benzoyl-β-D-Glucose) epipodophyllotoxin glucosides
Step 1: as shown in embodiment 1 step 1;
Step 2: the preparation of epipodophyllotoxin
Under nitrogen protection; by podophyllotoxin 1.0g; 2.41mmol and Sodium Bromide 993.2mg, 9.65mmol, be dissolved in 24mL acetonitrile; add methylsulfonic acid 0.63mL again; after 9.65mmol reaction system at room temperature stirs 1h, add 12mL water, then add barium carbonate 1.906g; 9.65mmol, stirring at room temperature is until react completely.Reaction system extraction is dry, and obtain thick product after concentrating under reduced pressure, column chromatography purification obtains target product 950mg, and 95%;
Step 3: the preparation of epipodophyllotoxin 4-O-(2,3,4,6-tetra--O-benzoyl-β-D-Glucose) epipodophyllotoxin glucosides
Under nitrogen protection, the glucose protected by full benzoyl is dissolved in dry 3mLDCM to body 230mg, 0.3mmol and epipodophyllotoxin 41mg, 0.1mmol, after reaction system at room temperature stirs 30min, adds Ph 3pAuNTf 215mg, 0.02mmol, stirring at room temperature is until react completely.Obtain thick product after reaction system concentrating under reduced pressure, column chromatography purification obtains target product 74.4mg, and 74.25%.[α] 26 D＝-0.209(c＝1.310inCHCl 3)； 1HNMR(400MHz,CDCl 3):δ8.10(d,J＝7.6Hz,2H),7.93(d,J＝7.6Hz,2H),7.84(d,J＝7.6Hz,2H),7.78(d,J＝7.56Hz,2H),7.59(t,J＝7.28Hz,1H),7.52(m,2H),7.46(t,J＝7.64Hz,3H),7.39(dd,J＝7.2,14.44Hz,6H),6.79(s,1H),6.36(s,1H),6.13(s,2H),5.93(d,J＝12.0Hz,2H),5.80(s,1H),5.71(t,J＝9.44Hz,1H),5.51(t,J＝9.44Hz,1H),5.04(d,J＝7.44Hz,1H),4.95(s,1H),4.54(d,J＝8.04Hz,1H),4.48(t,J＝9.16Hz,1H),4.33(d,J＝4.88Hz,1H),4.28(t,J＝7.48Hz1H),4.19(s,1H),3.77(s,3H),3.69(s,6H),3.10(dd,J＝5.2,14Hz,1H),3.84(m,1H)； 13CNMR(400MHzCDCl 3)δ174.4,166.1,165.7,165.2,165.0,152.5,148.6,146.8,133.6，133.3,133.1,129.8,129.8,129.7,129.5,128.6,128.6,128.5,128.5,128.3,110.9,108.9,108.2,101.5,98.8,73.4,72.4,71.8,69.5,67.6,62.8,60.7,56.3.HRMS(m/z):[M+Na] +calcdforC56H48Na +O171015.2784,found1015.2799。
Embodiment 3
The preparation of podophyllotoxin 4-O-(2,3,6-tri--O-benzoyl-β-L-rhamnosyl) podophyllotoxin glucosides
Step 1: full benzoyl protection rhamnosyl is to the preparation of body;
Under nitrogen protection; by the rhamnosyl 5g of full Bz protection exposed for different head position; 10.5mmol and adjacent alkynyl phenylformic acid 2.3g, 12.6mmol are dissolved in dry 12mLDCM, then in system, add EDCI2.3g; 11.6mmol; DMAP1.2g, 11.6mmol and DIPEA3.5ml, 19.5mmol; and track to reaction end in stirred at ambient temperature 3h, TLC.By thick for reaction system concentrating under reduced pressure product, then column chromatography obtains rhamnosyl alkynes ester to body 6.1g, and 93%;
Step 2: the preparation of podophyllotoxin 4-O-(2,3,6-tri--O-benzoyl-β-L-rhamnosyl) podophyllotoxin glucosides
Under nitrogen protection, the rhamnosyl protected by full benzoyl is dissolved in dry 3mLDCM to body 97mg, 0.15mmol and podophyllotoxin 41mg, 0.1mmol, after reaction system at room temperature stirs 30min, adds Ph 3pAuNTf 222mg, 0.03mmol, stirring at room temperature is until react completely.Obtain thick product after reaction system concentrating under reduced pressure, column chromatography purification obtains target product 86.7mg, and 98%.[α] 26 D＝+0.350(c＝0.914inCHCl 3)； 1HNMR(400MHz,CDCl 3):δ8.07(d,J＝8.0Hz,2H),8.01(d,J＝4.0Hz,2H),7.86(d,J＝8.0Hz,2H),7.62(m,7H),7.39(m,2H),7.14(s,2H),6.56(s,1H),6.39(s,2H),6.05(s,1H),5.93(dd,J＝4.0,12.0Hz,1H),5.77(t,J＝8.0Hz,1H),5.58(m,1H),5.20(d,J＝4.0Hz,1H),5.11(d,J＝12.0Hz,1H),4.69(t,J＝8.0Hz,1H),4.62(d,J＝4.0Hz,1H),3.39(m,1H),4.22(t,J＝8.0Hz,1H),3.80(s,3H),3.69(s,6H),3.23(m,1H),2.89(dd,J＝8.0,12.0Hz,1H),1.40(d,J＝8.0Hz,3H)； 13CNMR(400MHzCDCl 3)δ173.7,165.7,165.5,165.4,152.6,148.2,147.9,137.0,134.8，133.7,133.4,133.2,132.8,129.8,129.7(2C),129.2,129.1,129.0,128.6128.4,128.3,109.8,107.8,107.0,101.6,95.0,79.2,71.6,71.4,71.3,69.5,68.1,60.7,55.9,45.7,44.0,38.0,17.8.HRMS(m/z):[M+Na] +calcdforC49H44Na +O15O17895.2574,found895.2572。
Embodiment 4
The preparation of epipodophyllotoxin-4-O-(2,4,6-tri--O-benzoyl-β-L-rhamnosyl) epipodophyllotoxin glucosides
Step 1: synthetic method is as shown in embodiment 3 step 1;
Step 2: the preparation synthetic method of epipodophyllotoxin is as shown in embodiment 2 step 2;
Step 3: the preparation of epipodophyllotoxin-4-O-(2,4,6-tri--O-benzoyl-β-L-rhamnosyl) epipodophyllotoxin glucosides
Under nitrogen protection, the rhamnosyl protected by full benzoyl is dissolved in dry 3mLDCM to body 200mg, 0.3mmol and epipodophyllotoxin 41mg, 0.1mmol, after reaction system at room temperature stirs 30min, adds Ph 3pAuNTf 2(15mg, 0.02mmol), stirring at room temperature is until react completely.Obtain thick product after reaction system concentrating under reduced pressure, column chromatography purification obtains target product 115mg, and 98%.[α] 26 D＝+0.063(c＝1.40inCHCl 3)； 1HNMR(400MHz,CDCl 3):δ8.09(d,J＝8.0Hz,2H),7.99(d,J＝8.0Hz,2H),7.79(d,J＝8.0Hz,2H),7.64(m,1H),7.55(m,3H),7.42(m,3H),7.25(m,3H),6.99(s,1H),6.60(s,1H),6.26(s,2H),6.00(d,J＝8.0Hz,1H),5.73(d,J＝8.0Hz,2H),5.62(s,1H),5.19(s,1H),4.95(s,1H),4.71(d,J＝8.0Hz,1H),4.57(m,1H),4.08(m,1H),3.91(s,3H),3.81(s,6H),3.59(dd,J＝8.0,16.0Hz,1H),3.06(m,1H),1.48(d,J＝8.0Hz,3H)； 13CNMR(400MHzCDCl 3)δ174.4,165.7,165.4,152.6,149.0,146.8,137.3,135.4,133.6,133.5,132.9,132.7,132.6,132.2,132.0,129.9,129.6,129.5,129.3,125.9,111.5,110.3,108.3,101.6,94.0,77.2,71.4,71.5,70.0,68.0,67.0,60.7,56.3,44.0,40.8,37.7,17.9.HRMS(m/z):[M+Na] +calcdforC49H44Na +O15O17895.2574,found895.2572。
Embodiment 5
The preparation of 4-O-(2,3,4,6-tetra--O-benzoyl-β-D-semi-lactosi) podophyllotoxin glucosides
Synthetic method is as described in Example 1: 93.3%* α+ 26 d=-0.124 (c=1.166inCHCl 3) 1hNMR (400MHz, CDCl 3): δ 8.13 (d, J=7.6Hz, 2H), 7.93 (d, J=7.2Hz, 2H), 7.85 (d, J=7.2Hz, 2H), 7.77 (d, J=7.2Hz, 2H), 7.67 (t, J=7.6Hz, 2H), 7.54 (m, 4H), 7.45 (t, J=7.6Hz, 1H), 7.37 (m, 4H), 7.24 (s, 1H), 7.22 (d, J=3.2Hz, 1H), 6.49 (s, 1H), 6.33 (s, 2H), 6.01 (d, J=3.2Hz, 1H), 5.98 (s, 1H), 5.94 (s, 1H), 5.93 (dd, J=7.6, 10.4Hz, 1H), 5.65 (dd, J=3.2, 10.4Hz, 1H), 5.02 (d, J=10.0Hz, 1H), 4.95 (d, J=8.0Hz, 1H), 4.64 (dd, J=7.2, 11.6Hz, 1H), 4.54 (m, 3H), 4.35 (t, J=6.0Hz, 1H), 4.13 (t, J=8.8Hz, 1H), 3.78 (m, 1H), 3.73 (s, 6H), 3.67 (s, 3H), 2.94 (m, 1H), 2.78 (dd, J=4.8, 14.4Hz), 13cNMR (400MHzCDCl 3) δ 173.6,166.0,165.6,165.5,165.1,152.6,148.0,147.6,137.4,134.9,133.7,133.6,133.4,133.3,132.3,130.0,129.7,129.6,129.5,129.3,128.9 (2C), 128.7,128.6,128.5,128.4,128.3,109.5,108.5,108.1,101.4,99.6,80.0,71.9,71.5,71.1,69.7,68.2,62.3,60.5,56.4,45.4,43.9,38.7.HRMS (m/z): [M+Na] +calcdforC56H48Na +o171015.2784, found1015.2798.
Embodiment 6
The preparation of 4-O-(2,3,4,6-tetra--O-benzoyl-β-D-semi-lactosi) epipodophyllotoxin glucosides
Synthetic method is as described in Example 2: 80.3% [α] 26 d=+0.055 (c=0.63inCHCl 3) 1hNMR (400MHz, CDCl 3): δ 8.11 (d, J=7.2Hz, 2H), 8.07 (d, J=7.2Hz, 2H), 7.78 (m, 4H), 7.67 (t, J=7.6Hz, 1H), 7.60 (m, 5H), 7.75 (t, J=7.6Hz, 3H), 7.36 (t, J=7.6, 2H), 7.25 (d, J=7.6, 1H), 6.79 (s, 1H), 6.35 (s, 1H), 6.15 (s, 2H), 6.01 (d, J=3.2Hz, 1H), 5.91 (s, 1H), 5.77 (s, 1H), 5.75 (m, 1H), 5.65 (dd, J=3.2, 10.4Hz, 1H), 5.03 (d, J=7.6Hz, 1H), 4.96 (s, 1H), 4.74 (dd, J=6.8, 11.6Hz, 1H), 4.63 (s, 9H), 4.39 (m, 3H), 3.80 (s, 3H), 3.70 (s, 6H), 3.20 (dd, J=5.6, 14.0Hz), 2.90 (m, 1H), 13cNMR (400MHzCDCl 3) δ 174.5,166.0,165.6,165.5,165.0,152.5,148.5,146.8,137.2,135.1,133.7,133.4,133.3,133.1,132.8,130.0,129.8,129.7,129.5,129.3,129.0,128.8,128.7,128.6,128.5,128.3 (2C), 127.3,110.8,108.9,108.2,101.4,99.6,73.8,71.7,71.2,69.7,68.2,67.7,62.4,60.7,56.3,43.7,40.7,37.6,29.6.HRMS (m/z): [M+Na] +calcdforC56H48Na +o171015.2784, found1015.2785.
Embodiment 7
The preparation of 4-O-(2,3,5-tri--O-benzoyl-β-L-arabinose) podophyllotoxin glucosides
Step 1:2,3,5-tri--O-benzoyl-β-L-arabinose alkynes ester to the preparation of body
Under nitrogen protection; by the pectinose 1.3g of full Bz protection exposed for different head position; 2.8mmol and adjacent alkynyl phenylformic acid 0.78g, 4.2mmol are dissolved in dry 10mLDCM, then in system, add EDCI0.83g; 6.75mmol; DMAP0.52g, 5.4mmol and DIPEA0.98ml, 11.2mmol; and track to reaction end in stirred at ambient temperature 3h, TLC.By thick for reaction system concentrating under reduced pressure product, then column chromatography obtains glucose alkynes ester to body 1.67g, and 95%;
The preparation of step 2:4-O-(2,3,5-tri--O-benzoyl-β-L-arabinose) podophyllotoxin glucosides:
Synthetic method is as shown in embodiment 1 step 3: 95%, [α] 26 d=-0.871 (c=1.552inCHCl 3) 1hNMR (400MHz, CDCl 3): δ 8.11 (d, J=8.0Hz, 2H), 8.05 (d, J=4.0Hz, 2H), 8.01 (d, J=8.0Hz, 2H), 7.63 (m, 9H), 7.18 (s, 1H), 6.52 (s, 1H), 6.38 (s, 2H), 5.94 (s, 2H), 5.68 (d, J=4.0Hz, 2H), 5.53 (s, 1H), 5.38 (s, 1H), 5.04 (d, J=8.0Hz, 1H), 4.84 (m, 2H), 4.83 (dd, J=4.0, 8.0Hz, 1H), 4.59 (d, J=4.0Hz, 1H), 4.19 (t, J=12.0Hz, 1H), 3.78 (s, 3H), 3.69 (s, 6H), 3.14 (m, 1H), 2.88 (dd, J=4.0, 16.0Hz, 1H), 13cNMR (400MHzCDCl 3) δ 173.8,166.2,165.7,165.5,152.6,147.9,147.6,137.1,135.1,133.8,133.7,133.2,132.3,133.0129.9,129.8,129.6,128.6 (2C), 128.4,109.7,108.1,107.5,104.3,101.5,82.5,82.1,77.4,71.4,63.8,60.7,56.0,45.6,44.0,38.7.HRMS (m/z): [M+Na] +calcdforC48H42Na +o15881.2416, found881.2429.
Embodiment 8
The preparation of 4-O-(2,3,5-tri--O-benzoyl-β-L-arabinose) epipodophyllotoxin glucosides
Synthetic method is as described in Example 1: 88.3%, * α+ 26 d=-0.260 (c=1.064inCHCl 3) 1hNMR (400MHz, CDCl 3): 1hNMR (400MHz, CDCl 3): δ 8.07 (d, J=7.6Hz, 2H), 8.03 (dd, J=4.8, 7.2Hz, 4H), 7.61 (m, 2H), 7.50 (m, 4H), 7.43 (m, 2H), 7.34 (t, J=8.0Hz, 2H), 6.99 (s, 1H), 6.58 (s, 1H), 6.25 (s, 2H), 5.98 (d, J=12.8Hz, 1H), 5.60 (d, J=4.0Hz, 1H), 5.54 (d, J=5.2Hz, 2H), 5.54 (d, J=2.8Hz, 1H), 4.87 (dd, J=4.0, 12.0Hz, 1H), 4.74 (dd, J=5.2, 11.6Hz, 1H), 4.67 (d, J=5.2, 1H), 4.58 (m, 1H), 4.51 (m, 1H), 4.32 (t, J=5.2Hz, 1H), 3.83 (s, 3H), 3.74 (s, 6H), 3.55 (dd, J=5.2, 14.0Hz, 1H), 2.99 (m, 1H), 13cNMR (400MHzCDCl 3) δ 174.7,166.2,165.6,165.2,152.6,148.7,146.8,146.8,137.3,135.3,133.8,133.6,133.2,133.0129.9 (2C), 129.6,128.8,128.6,128.5,128.4,127.2,111.2,110.0,108.3,103.0,101.5,82.4,81.7,78.0,77.2,69.7,67.1,63.8,60.7,56.2,44.0,40.9,37.6.HRMS (m/z): [M+Na] +calcdforC48H42Na +o15881.2416, found881.2423.
Embodiment 9
The preparation of 4-O-(2,3,6-tri--O-benzoyl-β-D-ribose) podophyllotoxin glucosides
Synthetic method is as described in Example 7: 81.6%, 1[α] 26 d=-0.330 (c=0.85inCHCl 3), HNMR (400MHz, CDCl 3): δ 8.08 (d, J=4.0Hz, 2H), 7.98 (d, J=8Hz, 2H), 7.90 (d, J=4.0Hz, 2H), 7.58 (m, 4H), 7.430 (m, 3H), 7.44 (m, 6H), 7.13 (s, 1H), 6.51 (s, 1H), 6.37 (s, 2H), 5.93 (m, 1H), 5.70 (d, J=4.0Hz, 1H), 5.44 (s, 2H), 5.01 (d, J=12Hz, 1H), 4.79 (m, 2H), 4.69 (t, J=5.2Hz, 1H), 4.61 (m, 2H), 4.06 (t, J=12.0Hz, 1H), 3.79 (s, 3H), 3.68 (s, 6H), 3.12 (m, 1H), 2.83 (dd, J=4.0, 16.0Hz, 1H), 13cNMR (400MHzCDCl 3) δ 173.9,166.1,165.4,165.1,152.6,148.1,147.7,136.9,135.2,133.7,133.6,133.3,132.6,129.7 (3C), 129.5,129.4,128.8,128.7,128.5,128.4,109.7,107.9,107.3,102.9,101.5,79.6,79.0,77.2,72.0,71.4,64.4,60.7,55.9,45.6,44.0,37.9,31.5.HRMS (m/z): [M+Na] +calcdforC48H42Na +o15881.2416, found881.2422.
Embodiment 10
The preparation of 4-O-(2,3,6-tri--O-benzoyl-β-D-ribose) epipodophyllotoxin glucosides
Synthetic method is as described in Example 8: 78.5%, 1* α+ 26 d=-0.330 (c=0.85inCHCl 3), 1hNMR (400MHz, CDCl 3): δ 8.07 (d, J=7.2Hz, 2H), 8.02 (d, J=7.6Hz, 2H), 7.89 (d, J=7.6Hz, 2H), 7.61 (m, 3H), 7.45 (dd, J=7.2, 14Hz, 1H), 7.35 (t, J=7.2Hz, 2H), 6.70 (s, 1H), 6.55 (s, 1H), 6.22 (s, 2H), 5.99 (d, J=10.0Hz, 1H), 5.81 (m, 1H), 5.65 (d, J=4.8Hz, 1H), 5.41 (s, 1H), 5.00 (d, J=2.0Hz, 1H), 4.11 (t, J=7.6Hz, 1H), 3.80 (s, 3H), 3.73 (s, 6H), 3.36 (dd, J=5.6, 14.4Hz, 1H), 2.88 (m, 1H), 13cNMR (400MHzCDCl 3) δ 174.5,166.1,165.3,165.1,152.5,148.7,146.7,135.3,133.6,133.5,133.4,133.3,129.8,129.7 (2C), 129.5,129.0,128.7,128.5 (2C), 128.4,126.7,111.2,110.3,108.3,102.6,101.5,79.4,77.2,75.7,72.0,71.1,67.1,64.3,60.7,56.3,53.4,43.9,40.7,37.6.HRMS (m/z): [M+Na] +calcdforC48H42Na +o15881.2416, found881.2428.
Embodiment 11
The preparation of Etoposide
Step one, the required preparation of giving body of compound
1, N 2under protection; be the glucose 2.0g that other position hydroxyls of p methoxy phenol protection are exposed by different head position; 7.02mmol is dissolved in the acetonitrile of 110mL drying; add dimethylacetal 1.06mL; 10.05mmol and tosic acid 72.8mg, 0.4mmol, room temperature reaction spends the night; to system clarification, TLC tracks to reaction to be terminated.Triethylamine cancellation is reacted, and by thick for reaction system concentrating under reduced pressure product, then column chromatography obtains product 2.45g, and 92%; * α+ 28 d=-0.71 (c1.02, MeOH); 1hNMR (400MHz, CD 3oD) δ 7.02 (d, J=9.2Hz, 2H), 6.84 (d, J=9.2Hz, 2H), 4.84 (s, 1H), (4.77 q, J=5.2Hz, 1H), 4.13 (dd, J=4.8,10.0Hz, 1H), 3.74 (s, 3H), 3.65 (t, J=8.8Hz, 1H), 3.57 (t, J=10.0Hz, 1H), 3.49 (dd, J=7.6,8.8Hz, 1H), 3.42-3.35 (m, 1H), 3.32-3.30 (m, 1H), 1.32 (d, J=5.2Hz, 3H); 13cNMR (100MHz, CD 3oD) δ 156.8,152.9,119.4,115.5,103.9,100.7,81.6,75.8,74.5,69.1,67.6,56.0,20.6; HRMS (MALDI) calcdforC 15h 24o 7n [M+NH 4] +330.1548, found330.1547.
2, by products therefrom 160mg, 0.51mmol, with AZMB acid 272.45mg, 1.54mmol, and adjacent alkynyl phenylformic acid 1.87g, 10.1mmol is dissolved in dry 3mLDCM, then in system, adds DMAP238.2mg, 1.95mmol, DIPEA0.72mL, 4.14mmol, and EDCI472mg, 2.46mmol, and track to reaction end in stirred at ambient temperature 3h, TLC.By thick for reaction system concentrating under reduced pressure product, then column chromatography obtains product 291mg, and 90%.* α+ 28 d=0.26 (c1.0, CHCl 3), 1hNMR (400MHz, CDCl 3) δ 8.00 (dd, J=1.2, 8.0Hz, 1H), 7.95 (dd, J=1.2, 8.0Hz, 1H), 7.57-7.52 (m, 2H), 7.47-7.35 (m, 4H), 6.94 (d, J=9.2Hz, 2H), 6.80 (d, J=9.2Hz, 2H), 5.74 (t, J=9.2Hz, 1H), 5.65 (dd, J=7.6, 9.2Hz, 1H), 5.24 (d, J=8.0Hz, 1H), 4.78 (q, J=5.2Hz, 1H), 4.72-4.60 (m, 4H), 4.31 (dd, J=4.4, 10.4Hz, 1H), 3.82 (t, J=9.2Hz, 1H), 3.75 (s, 3H), 3.73 (t, J=10.0Hz, 1H), 3.66-3.62 (m, 1H), 1.36 (d, J=5.2Hz, 3H), 13cNMR (100MHz, CDCl 3) δ 165.8,165.2,155.9,150.8,137.6,137.4,133.1,133.0,131.1,131.0,129.6,128.2,127.9,118.8,114.6,101.0,99.9,78.0,72.6,72.4,68.1,66.7,55.6,52.8 (2C), 20.2, HRMS (MALDI) calcdforC 31h 34n 7o 9[M+NH 4] +648.2411, found648.2413.3, is dissolved in acetonitrile/toluene/H by upper step products therefrom 1.34g, 2.18mmol 2oV/V/V=1.5:1:1,24.5mL, add CAN5.8g at 0 DEG C, 10.7mmol, rise to room temperature afterwards, reacts 15 minutes.TLC tracks to reaction to be terminated, diluted ethyl acetate, washing twice, NaHCO 3wash twice, saturated NaCl washes, anhydrous sodium sulfate drying, column chromatography obtains different head position exposed product 1.1g, 2.1mmol, adjacent alkynyl phenylformic acid 479.1mg, 2.6mmol is dissolved in dry 12mLDCM, then in system, DIPEA1.5mL is added, 8.6mmol, DMAP497.7mg, 4.1mmol, and EDCI986.4mg, 5.1mmol and in stirred at ambient temperature 3h, TLC track to reaction terminate.By thick for reaction system concentrating under reduced pressure product, then column chromatography obtains required to body 1.34g, and 90%.*α+ 28 D＝0.59(c1.1,CHCl 3)； 1HNMR(400MHz,CDCl 3)δ7.97(dd,J＝1.2,4.4Hz,1H),7.95(dd,J＝1.2,4.4Hz,1H),7.90(dd,J＝0.8,7.6Hz,1H),7.57-7.18(m,9H),6.21(d,J＝8.0Hz,1H),5.80(t,J＝9.2Hz,1H),5.72(dd,J＝8.0,9.2Hz,1H),4.78(q,J＝4.8Hz,1H),4.72(AB,2H),4.57(AB,2H),4.34(dd,J＝4.4,10.4Hz,1H),3.83-3.74(m,2H),3.68(t,J＝10.0Hz,1H),1.53-1.50(m,1H),1.36(d,J＝5.2Hz,3H),0.92-0.86(m,4H)； 13CNMR(100MHz,CDCl 3)δ165.6,165.1,163.1,137.5,137.4,134.5,133.2,133.0,132.6,131.1,131.0,130.7,129.6,129.5,129.0,128.9,128.2(2C),128.1(2C),127.3,127.0,125.9,100.7,99.9,92.6,77.9,74.2,72.3,71.5,67.8,67.3,52.7,20.2,8.96,0.65；HRMS(MALDI)calcdforC 36H 36N 7O 9[M+NH 4] +710.2568,found710.2569.
Step 2, the preparation of the appropriate protection base of 4 ' position hydroxyl of 4 ' de-methoxy epipodophyllotoxin
Get 4 ' de-methoxy epipodophyllotoxin 40mg, 0.1mmol is dissolved in dry DCM, adds triethylamine 0.02mL, 0.15mmol, adds chloroformic acid benzyl ester 0.02mL, 0.15mmol, and room temperature reaction 3h.TLC monitors reaction and terminates, and column chromatography obtains white solid.
Step 3, the structure of glycosidic link
Under nitrogen protection, by 4 ' the de-methoxy epipodophyllotoxin 53mg being protected to body 204mg, 0.3mmol and 4 ' position hydroxyl by Cbz prepared above, 0.1mmol is dissolved in dry 3mLDCM, after reaction system at room temperature stirs 30min, adds Ph 3pAuOTf 2(1mL, 0.02M) reaction is spent the night, and TLC reacts end, and filter, column chromatography obtains white solid 85.6mg, 82.3%, * α+ 28 d=-0.18 (c1.0, CHCl 3), 1hNMR (400MHz, CDCl 3) δ 7.86 (dd, J=1.6, 8.0Hz, 1H), 7.58 (dd, J=1.6, 8.0Hz, 1H), 7.47-7.41 (m, 2H), 7.37-7.23 (m, 9H), 6.60 (s, 1H), 6.30 (s, 1H), 6.12 (s, 2H), 5.80 (d, J=1.6Hz, 1H), 5.66 (d, J=1.6Hz, 1H), 5.63 (t, J=9.6Hz, 1H), 5.29 (dd, J=8.0, 9.6Hz, 1H), 5.16 (s, 2H), 4.98 (d, J=7.6Hz, 1H), 4.79 (d, J=3.2Hz, 1H), 4.70 (t, J=4.8Hz, 1H), 4.58 (s, 2H), 4.20-4.34 (m, 3H), 4.27 (AB, 1H), 4.21-4.16 (m, 2H), 3.66 (t, J=9.2Hz, 1H), 3.62 (t, J=10.0Hz, 1H), 3.56 (s, 6H), 3.52-3.46 (m, 1H), 3.13 (dd, J=5.2, 14.0Hz, 1H), 2.80-2.71 (m, 1H), 1.28 (d, J=5.2Hz, 3H), 13cNMR (100MHz, CDCl 3) δ 174.3,165.7,164.8,153.0,151.4,148.6,146.9,138.0,137.5,137.2,135.0,133.0,132.8,132.0,130.9,130.8,129.7,129.3,128.4 (2C), 128.3,128.1,127.9 (2C), 127.4,110.7,108.6,107.6,101.5,100.0,99.9,78.0,74.2,72.4,71.8,70.2,67.9,67.4,66.6,56.1,52.7,52.6,43.7,40.7,37.4,20.1, HRMS (MALDI) calcdforC 53h 48n 6o 15na [M+Na] +1063.2967, found1063.2968.
Step 4, removing of protecting group
Get previous step glycosylation product 56.2mg, 0.054mmol and be dissolved in MeOH and Isosorbide-5-Nitrae-dioxanev/v=3:1,8mL, add HCO 2nH 440.9mg, 0.65mmol and 10%Pd-C. track to reaction at 30 DEG C of reactions 4h, TLC to be terminated, and diatomite filtered through silica gel, diluted ethyl acetate, wash three times, saturated sodium-chloride washes twice, anhydrous sodium sulfate drying.Column chromatography obtain white solid Etoposide.* α+ 28 d=-0.63 (c1.0, CHCl 3), 1hNMR (400MHz, CDCl 3) δ 6.82 (s, 1H), 6.54 (s, 1H), 6.25 (s, 2H), 6.00 (d, J=1.2Hz, 1H), 5.98 (d, J=1.2Hz, 1H), 5.42 (brs, 1H), 4.91 (d, J=3.2Hz, 1H), 4.77 (q, J=4.8Hz, 1H), 4.66 (d, J=7.6Hz, 1H), 4.60 (d, J=5.2Hz, 1H), 4.44 (dd, J=9.2, 10.8Hz, 1H), 4.24 (t, J=8.4Hz, 1H), 4.19 (dd, J=4.0, 10.4Hz, 1H), 3.76 (s, 6H), 3.74 (m, 1H), 3.60-3.55 (m, 1H), 3.46 (dd, J=7.6, 8.8Hz, 1H), 3.37-3.83 (m, 2H), 3.28 (dd, J=5.2, 14.0Hz, 1H), 2.93-2.84 (m, 1H), 2.05 (bs, 2H), 1.40 (d, J=4.8Hz, 3H), 13cNMR (100MHz, CDCl 3) δ 174.9,148.9,147.2,146.4,134.1,132.8,130.4,128.3,110.7,108.9,107.9,102.1,101.6,99.8,79.7,74.5,74.0,73.1,56.5,43.7,41.3,37.4,20.3, HRMS (MALDI) calcdforC 29h 32o 13na [M+Na] +611.1731, found611.1735.
Embodiment 12
The preparation of teniposide
Step one, the required preparation of giving body of compound
N 2under protection, be the glucose 1.42g that other position hydroxyls of p methoxy phenol protection are exposed by different head position, 4.98mmol is dissolved in dry 18mL2-thiophenecarboxaldehyde, adds anhydrous ZnCl 23.4g, 12.46mmol30 DEG C of reaction is spent the night, DCM diluted system, washing, saturated NaHCO 3wash, anhydrous sodium sulfate drying.Column chromatography for separation 1.41g, 74.5%:* α+ 28 d=-0.08 (c1.0, MeOH); 1hNMR (400MHz, CDCl 3) δ 7.31 (d, J=4.8Hz, 1H), 7.17 (d, J=3.2Hz, 1H), 7.01-6.97 (m, 3H), 6.84 (d, J=9.2Hz, 2H), 5.80 (s, 1H), 4.89 (d, J=7.6Hz, 1H), 4.35 (dd, J=4.8,10.4Hz, 1H), 3.91 (t, J=8.8Hz, 1H), 3.82-3.72 (m, 2H), 3.77 (d, 3H), 3.63 (t, J=8.8Hz, 1H), 3.56-3.50 (m, 1H), 2.77 (brs, 1H), 2.69 (brs, 1H); 13cNMR (100MHz, CDCl 3) δ 182.8,156.0,151.0,139.5,136.0,135.0,128.3,126.5,126.2,126.0,118.8,114.8,102.6,98.8,80.5,74.6,73.3,68.7,66.4,55.7; HRMS (MALDI) calcdforC 18h 21o 7s [M+H] +381.1004, found381.1003.2, preparation method with in embodiment 11 step one, 2; Column chromatography obtains product 2.5g, and 91%.[α] 28 D＝0.05(c0.8,CHCl 3)； 1HNMR(400MHz,CDCl 3)δ7.98-7.96(m,2H),7.57-7.52(m,2H),7.47(dd,J＝2.8,7.6Hz,2H),7.42-7.36(m,2H),7.30(dd,J＝1.2,5.2Hz,1H),7.12(m,1H),6.98-6.94(m,3H),6.82(d,J＝9.2Hz,2H),5.85(td,J＝9.6,2.0Hz,1H),5.83(s,1H),5.71(td,J＝7.6,2.4Hz,1H),5.29(dd,J＝1.6,8.0Hz,1H),4.73(m,4H),4.48(dd,J＝4.8,10.8Hz,1H),4.05(t,J＝9.2Hz,1H),3.95(t,J＝10.0Hz,1H),3.83-3.78(m,1H),3.76(s,3H)； 13CNMR(100MHz,CDCl 3)δ165.6,165.1,155.9,150.7,139.0,137.6,137.3,133.1,132.9,131.0,130.9,129.6,129.5,128.2(2C),128.1,127.8,126.5,126.1,125.7,118.7,114.6,101.0,98.6,78.3,72.5,72.1,68.4,66.4,55.6,52.8,52.7；HRMS(MALDI)calcdforC 34H 31O 9N 6S[M+H] +699.1871,found699.1868.
3, by upper step products therefrom 1.5g, 2.16mmol is dissolved in acetonitrile/H 2oV/V=9:1,15mL, add NaHCO 3181mg, 2.16mmol, add CAN2.48g at 0 DEG C, 2.1mmol, and 0 DEG C is reacted 15 minutes.TLC tracks to reaction to be terminated, diluted ethyl acetate, washing twice, NaHCO 3wash twice, saturated NaCl washes, anhydrous sodium sulfate drying, column chromatography obtains the exposed product 800mg in different head position, 1.5mmol, adjacent alkynyl phenylformic acid 341mg, 1.8mmol are dissolved in dry 8mLDCM, then in system, DIPEA1.1mL is added, DMAP354mg, 2.86mmol, and EDCI702mg, 6mmol also tracks to reaction end in stirred at ambient temperature 3h, TLC.By thick for reaction system concentrating under reduced pressure product, then column chromatography obtains required to body 870mg, and 75%.α/β＝1:5 1HNMR(400MHz,CDCl 3)δ8.02(dd,J＝1.2,8.0Hz,0.2H),7.98-7.91(m,3.20H),7.88(dd,J＝1.2,7.6Hz,0.2H),7.56-7.27(m,12H),7.13(d,J＝3.2Hz,1H),7.10(d,J＝3.2Hz,0.2H),6.98-6.95(m,1.2H),6.84(d,J＝4.0Hz,0.2H),6.26(d,J＝8.0Hz,1H),6.23(t,J＝10.0Hz,0.2H),5.90(t,J＝9.6Hz,1H),5.86(s,0.2H),5.83(s,1H),5.77(dd,J＝8.4,9.2Hz,1H),5.65(dd,J＝4.0,10.0Hz,0.2H),4.74-4.63(m,0.8H),4.64(s,2H),4.60(AB,2H),4.51(dd,J＝4.0,9.6Hz,1H),4.52-4.42(m,0.4H),4.06-4.01(m,1.2H),3.97-3.86(m,2.2H),1.56-1.49(m,1.2H),0.93-0.84(m,4.8H)； 13CNMR(100MHz,CDCl 3)δ165.6,165.3,165.1,164.3,163.1,139.1,138.9,138.0,137.6,137.3,137.1,135.0,134.5,133.3(2C),133.0,132.9,132.7,132.5,131.5,131.2,130.9,130.8,129.6(3C),129.3,128.9,128.3,128.2,128.1,127.3,127.2,127.0,126.8,126.2,126.1,125.9,125.7(2C),125.2,100.7,98.8,98.7,92.7,90.5,78.8,78.3,77.2,74.8,74.2,72.2,71.5,70.7,69.9,68.5,68.3,67.1,65.2,52.9,52.8,52.7,9.2,8.9,0.8,0.7；HRMS(MALDI)calcdforC 39H 32O 9N 6SNa[M+Na] +783.1843,found783.1744.
Step 2, the preparation preparation method of the appropriate protection base of 4 ' position hydroxyl of 4 ' de-methoxy epipodophyllotoxin is with example 11 step 2
Step 3, the structure of glycosidic link
Preparation method with embodiment 11 step 2 obtain white solid 83.9%* α+ 28 d=-0.12 (c1.1, CHCl 3), 1hNMR (400MHz, CDCl 3) δ 7.91 (d, J=7.6Hz, 1H), 7.67 (d, J=7.6Hz, 1H), 7.54 (t, J=7.6Hz, 2H), 7.44-7.30 (m, 10H), 7.12 (d, J=2.8Hz, 1H), 6.98 (dd, J=4.0, 4.8Hz, 1H), 6.69 (brs, 1H), 6.39 (s, 1H), 6.19 (s, 2H), 5.89 (s, 1H), 5.82 (s, 1H), 5.78 (t, J=10.0Hz, 1H), 5.75 (s, 1H), 5.42 (dd, J=7.6, 9.6Hz, 1H), 5.24 (s, 2H), 5.10 (d, J=6.8Hz, 1H), 4.90 (brs, 1H), 4.66 (AB, 2H), 4.52-4.34 (m, 5H), 4.29 (brs, 1H), 3.96-3.88 (m, 2H), 3.74 (brs, 1H), 3.64 (s, 6H), 3.22 (dd, J=5.2, 13.6Hz, 1H), 2.85 (brs, 1H), 13cNMR (100MHz, CDCl 3) δ 174.3,165.7,164.9,153.1,151.5,148.7,147.0,138.9,138.0,137.6,137.2,135.0,133.0 (2C), 132.1,130.9 (2C), 129.7,129.4,128.5 (2C), 128.4,128.2 (2C), 128.0,127.8,127.4,126.6,126.2,125.8,110.8,108.7,107.6,101.6,100.2,98.7,78.5,77.2,74.4,72.4,71.7,70.4,68.4,67.5,66.6,56.2,52.8,52.7,43.8,40.8,37.5, HRMS (MALDI) calcdforC 56h 48o 17n 6sNa [M+Na] +1131.2657, found1131.2689.
Step 4, removing of protecting group
Preparation method, with embodiment 11 step 3, obtains white solid Teniposide.82.9%, * α+ 28 d=-0.46 (c0.6, MeOH), 1hNMR (400MHz, DMSO-d 6) δ 8.27 (s, 1H), 7.56 (dd, J=1.2, 4.8Hz, 1H), 7.17 (d, J=2.8Hz, 1H), 7.03-7.01 (m, 2H), 6.53 (s, 1H), 6.18 (s, 2H), 6.04 (s, 1H), 6.02 (d, 1H), 5.88 (s, 1H), 6.32 (brs, 1H), 5.29 (d, J=5.2Hz, 1H), 4.95 (d, J=3.2Hz, 1H), 4.64 (d, J=7.6Hz, 1H), 4.50 (d, J=5.6Hz, 1H), 4.28-4.23 (m, 3H), 3.77 (dd, J=9.2, 10.0Hz, 1H), 3.61 (s, 6H), 3.42-3.40 (m, 3H), 3.32 (dd, J=5.6, 14.4Hz, 1H), 3.11-3.09 (m, 1H), 2.92-2.88 (m, 1H), 13cNMR (100MHz, DMSO-d 6) δ 174.1,147.1,146.5,139.7,134.1,132.2,129.6,128.1,125.8,125.7,125.3,109.3,109.2,107.8,100.8,100.7,96.9,79.9,73.8,72.0,71.2,67.2,67.0,65.0,55.4,42.3,39.8,36.6, HRMS (MALDI) calcdforC 32h 32o 13sNa [M+Na] +679.1469, found679.1456.
Above-described embodiment is only be described the preferred embodiment of the present invention; not scope of the present invention is limited; under not departing from the present invention and designing the prerequisite of spirit; the various distortion that those of ordinary skill in the art make technical scheme of the present invention and improvement, all should fall in protection domain that claims of the present invention determines.

Claims (5)

1. the preparation method of an Etoposide and teniposide and analogue thereof, with podophyllotoxin and 4 ' demethyl epipodophyllotoxin, epipodophyllotoxin, podophyllotoxin is raw material, it is characterized in that, comprise the steps (2) ~ (3) or step (1) ~ (3)
(1) with 4 ' demethyl epipodophyllotoxin for raw material, introduce R 1optionally protect 4 ' position hydroxyl, obtain the epipodophyllotoxin analog derivative 3 of 4 ' position hydroxyl protection,
Wherein, R 1for the hydroxyl protecting group that this area is conventional, described protecting group is preferably benzyl, t-Butyldimethylsilyl, methyl;
The epipodophyllotoxin analog derivative of (2) 4 ' position hydroxyl protections and 4 hydroxyls of podophyllotoxin acceptor occur glycosylation, and 4 that obtain full guard connect glycosyl R 2epipodophyllotoxin and podophillotoxines glucosides 2,
Wherein R 2for the β-D-Glucose base of full guard, the alpha-D-glucose base of full guard, β-D-the galactosyl of full guard, α-D-the galactosyl of full guard, β-D-MANNOSE the base of full guard, α-D-MANNOSE the base of full guard, β-D-the xylosyl of full guard, the alpha-D-xylose base of full guard, β-D-2-aminoglucose the glycosyl of full guard, α-D-2-aminoglucose the glycosyl of full guard, α-L-the rhamanopyranosyl of full guard, β-L-the rhamanopyranosyl of full guard, α-D-ribose the base of full guard, β-D-ribose the base of full guard, α-L-the ribosyl of full guard, β-L-the ribosyl of full guard, α-D-R the base of full guard, β-D-R the base of full guard, α-L-arabinose the base of full guard, β-L-arabinose the base of full guard, α-L-fucose the base of full guard, β-L-fucose the base of full guard, β-D-Glucose aldehydic acid the base of full guard, the alpha-D-glucose aldehydic acid base of full guard, β-D-galacturonic the acidic group of full guard, or the α-D-galacturonic acidic group of full guard, protecting group wherein on sugar is ethanoyl, benzoyl, benzyl, acetaldehyde fork, and thiophene aldehyde fork, AZMB structure are deng,
The epipodophyllotoxin of (3) 4 ' position hydroxyl protections and podophyllotoxin derivative glucosides deprotection base obtain Etoposide and teniposide and analogue 1 thereof,
2. the preparation method of a kind of Etoposide according to claim 1 and teniposide and analogue thereof, is characterized in that, each step is as follows:
Described step (1) 4 ' demethyl epipodophyllotoxin 4 ' position hydroxyl protecting group R 1introducing in, 4 ' demethyl epipodophyllotoxin with containing the reactant R of protecting group 1the mol ratio of X is 1:1.0-1.5, and temperature of reaction is-10-25 DEG C, and the reaction times is 0.5-12 hour, the organic solvent of reaction is selected from haloalkane, triethylamine, pyridine, the N of C1-C4, at least one in dinethylformamide, react and carry out under the effect of alkali, X is selected from halogen; The mol ratio 1:1.0-1.5 of epipodophyllotoxin and alkali;
In the described epipodophyllotoxin analog derivative of step (2) 4 ' position hydroxyl protection and 4 hydroxyl glycosylation reactions of podophyllotoxin acceptor; 4 secondary hydroxyl acceptors and glycosyl alkynes ester to body 4 in organic solvent with under protection of inert gas; glycosylation reaction is there is under Lewis acid effect
Described glycosyl alkynes ester to body is 4, R 3be selected from the alkyl of C1-C6, C3-C10 cycloalkyl or aryl;
The epipodophyllotoxin analog derivative acceptor 3 of 4 ' described position hydroxyl protection and podophyllotoxin acceptor, glycosyl alkynes ester are 1:21.05-53.0:0.051-0.05 to body 4, lewis acidic mol ratio, temperature of reaction is room temperature, reaction times is 0.54-12 hour, and the organic solvent of reaction is selected from least one in toluene, methylene dichloride, ether and acetonitrile;
Wherein R 1, R 2as claimed in claim 1.
3. a kind of Etoposide according to claim 1 and 2 and the preparation method of teniposide and analogue thereof, it is characterized in that, the alkali of described step (1) is selected from pyridine, triethylamine, DMAP, ethamine, imidazoles, sodium hydride, potassium hydride KH, lithium diisopropylamine or lithium hexamethyldisilazide; The Lewis acid of described step (3) is Au catalyst or molecular sieve, and Au catalyst is AuCl, AuCl 3, PPh 3auOTf or PPh 3auNTf 2, OTf is trifyl, NTf 2be that two trifyls are amino; Molecular sieve is molecular sieve or pickling molecular sieve, the mass ratio of substrate and molecular sieve is 1:2-10, and rare gas element is high-purity nitrogen, argon gas or helium.
4. a kind of Etoposide according to claim 1 and 2 and the preparation method of teniposide and analogue thereof, is characterized in that, described R 2for wherein Bz is benzoyl, and TBDPS is that the phenylbenzene tertiary butyl is silica-based, and AZMB is
5. a kind of Etoposide according to claim 1 and 2 and the preparation method of teniposide and analogue thereof, is characterized in that, described R 3for or
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