CN1821260A - Cholest compound, synthetic method and its use - Google Patents
Cholest compound, synthetic method and its use Download PDFInfo
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- CN1821260A CN1821260A CN 200610025050 CN200610025050A CN1821260A CN 1821260 A CN1821260 A CN 1821260A CN 200610025050 CN200610025050 CN 200610025050 CN 200610025050 A CN200610025050 A CN 200610025050A CN 1821260 A CN1821260 A CN 1821260A
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Abstract
The present invention relates to a kinds of C-27 steroid molecules with novel cholesterol skeleton structure, their synthesis process and use in synthesizing OSW-1 analogs, 22-deoxy-OSW-1 and 17,22-deoxy-OSW-1. These cholest compounds have the structure as shown, and the synthesis process of the present invention has easy operation and high atomic economical efficiency.
Description
Technical field
The present invention relates to the steroidal molecule with cholesterol skeleton of a class formation novelty, relate to the synthetic method of this compounds, with and in synthetic OSW-1 analogue 22-deoxidation-OSW-1 and 17, the purposes among 22-deoxidation-OSW-1.Utilize method of the present invention to synthesize the OSW-1 analogue, easy and simple to handle, have Atom economy more.
Technical background
1992, the Y.Sashida research group of Tokyo University medicine institute isolates a series of saponins with cholesterol skeleton from the underground bulb of a kind of evergreen ornamental plant Ornithogalum saunderside that originates in South Africa, they just the 3-position of glucoside unit and disaccharides aglucon 2 "-slightly different on the position; all have extremely strong anti-tumor activity; the OSW-1 (compound 1) as main extract has extremely strong lethality to multiple malignant cell, than present clinical employed several cancer therapy drugs such as mitomycin (Mitomycin); Zorubicin (Adriamycin); the effectiveness of taxol (Taxol) etc. exceeds 10-100 times.What is more important, though OSW-1 has good active to multiple malignant cell, it is to the but very little (IC of the murder by poisoning of people's normal lung cell
501500nM) (referring to Phytochemistry, 1992,31,3969; Bioorg.﹠amp; Med.Chem.Lett., 1997,7,633), its concrete structure is as follows:
Since extremely strong antitumour activity that OSW-1 had with and the unique chemical structure, and it is less to contain the plant resources of this compound, so the chemosynthesis of this compounds has caused extensive concern.At present, existing five groups finished OSW-1 and glucoside unit thereof synthetic (P.L.Fuchs group: referring to Tetra.Lett., 1998,39,1099; Hui Yongzheng group: referring to J.Org.Chem., 1999,64,202; Z.D.Jin group: referring to J.Arm.Chem.Soc., 2002,124,6576; J.W.Morzycki group: referring to Carbohydrate Res., 2002,337,1269 and Tian Weisheng group: referring to Tetra.Lett., 2003,44,9375).
For the relation between research structure and the activity more in depth, many OSW-1 and glucoside unit analogue thereof are synthesized out, but wherein many analogues do not have activity or activity very weak, Yu Biao group finds: the anti-tumor activity of 16 Alpha-hydroxies-OSW-12 is very weak, the biological activity ratio OSW-1 of 23-oxa--OSW-13 is high 100 times, 5,6-two hydrogen-OSW-14,22-deoxidation-OSW-15 and 26, the biological activity of 27-demethyl-OSW-16 also is higher than OSW-1.
Wherein, Ac is an ethanoyl, and MBz is to anisoyl.
Yu Biao group is a starting raw material with dehydroepiandros-sterone 8, goes on foot with 12 and has synthesized 22-deoxidation-OSW-15 with 1.26% total recovery:
Wherein, Ac and MBz as previously mentioned, TBS is that tertiary butyl dimethyl is silica-based, Ts is a p-toluenesulfonyl, TES is that triethyl is silica-based.
Dehydroepiandros-sterone 8 then by natural diosgenin (diosgenin) through six-step process degraded, total recovery between 25-50% (referring to J.Arm.Chem.Soc., 1940,62,3350; J.Org.Chem., 1956,21,520):
A, Ac
2O, 200 ℃; B, CrO
3, HOAc; C, NaOAc; D, oxammonium hydrochloride; E, p-acetaminobenzenesulfonyl chloride; F, K
2CO
3, MeOH.
Obviously, this synthesis strategy of steroid sapogenines that utilizes has a lot of shortcomings,, complex operation step outmoded such as degradation technique, environmental pollution are serious or the like, the more important thing is that the carbon skeleton of steroid sapogenines and functional group thereof fail to be fully used, and this must cause the significant wastage of resource.
People such as Tian Weisheng are devoted for years to the reasonable utilization research in the resource compound, the particularly reasonable utilization of steroid sapogenines, they have developed a kind of method (CN02145066.8) of directly utilizing the synthetic OSW-1 glucoside unit of diosgenin complete skeleton, on this basis, the present invention abides by the principle of Atom economy and carries out the chemical conversion of resource compound, with the diosgenin is raw material, utilize its complete skeleton and existing functional group to synthesize a series of C-27 steroidal molecules with cholesterol skeleton, these compounds can further be used for Synthetic 2 2-deoxidation-OSW-1 and 17,22-deoxidation-OSW-1.
Summary of the invention
The purpose of this invention is to provide cholest compound.
Another object of the present invention provides the method for synthetic above-mentioned courage steroid compound.
Purpose of the present invention also provides the purposes of above-mentioned steroidal compounds, and these compounds can be used for Synthetic 2 2-deoxidation-OSW-1 and 17,22-deoxidation-OSW-1.
The structure of courage steroid compound of the present invention is as follows:
R
1Be H, MOM, Bn, THP, Ac, Bz, Piv, TMS, TES, PMB or TBDPS; R
2Be H or OH; R
3Be H, OH, OMe, OTMS, OAc or and R
4Become carbonyl; R
4Be H or and R
3Become carbonyl; R
5Be H, OMs or OTs;
Work as R
1, R
2And R
4Be H and R
3During for OH, R
5Can not be OH or OTs;
Work as R
1, R
2, R
4And R
5During for H, R
3Can not be OH or OAc;
Work as R
3With R
4Become carbonyl and R
2And R
5During for H, R
1Can not be H, Ac or Bz;
Wherein, MOM is the methoxy methylene radical, and Bn is a benzyl; THP is a THP trtrahydropyranyl; Ac is an ethanoyl, and Bz is a benzoyl, and Piv is a pivaloyl group; TMS is trimethyl silicon based; TES is that triethyl is silica-based, and TBS is that tertiary butyl dimethyl is silica-based, and TBDPS is that tert-butyl diphenyl is silica-based; Ms is a methylsulfonyl, and Ts is a p-toluenesulfonyl.
Courage steroid compound of the present invention is synthetic by method A, method A～B, method A～C, method A～D, method A～E or method A～F:
R wherein
1Described as defined above, R
6Be Ms or Ts;
Diosgenin and hydroxyl protection reagent just can obtain compound 9 according to the method reaction of routine;
Method A: in alcoholic solvent, assistant agent is arranged or do not have assistant agent in the presence of, compound 9 stirs 0.2～24h with zinc powder and acid under O ℃～reflux temperature, obtain compound 10, the mol ratio of compound 9, zinc powder, acid and assistant agent is 1: 50～250: 50～500: 0～0.5, described acid is organic acid, mineral acid or their mixture, as acetate, trifluoroacetic acid, phenylformic acid, tosic acid (TsOH), camphorsulfonic acid (CSA), HCl, H
2SO
4Perhaps their mixture, described assistant agent is HgCl
2, HgBr
2, HgSO
4Perhaps HgO;
Method B: under-10～50 ℃ of non-protonic solvent neutralizations, under organic base catalytic, compound 10 generates sulphonate 11 with SULPHURYL CHLORIDE reaction 1～24h, the mol ratio of compound 10, SULPHURYL CHLORIDE and organic bases is 1: 1～5: O.5～2, described organic bases is 1,8-diazabicylo [5,4,0] 11-7-alkene (DBU), pyridine, 4-Dimethylamino pyridine (DMAP), bipyridine, lutidine (lutidine), trimethylpyridine (collidine) or have C
1～18The primary amine of alkyl, secondary amine or tertiary amine, described SULPHURYL CHLORIDE are methylsulfonyl chloride (MsCl) or Tosyl chloride (TsCl);
Method C: in non-protonic solvent, compound 11 and Li-Al hydrogen (LAH) generate compound 12 at-78-50 ℃ of reaction 0.2～15h down, and compound 11 is 1: 0.25～10 with the mol ratio of LAH;
Method D: compound 12 is dissolved in the organic solvent, adds oxygenant, assistant agent is arranged or do not have assistant agent in the presence of,-78～60 ℃ of reactions O.1～24h, obtain compound 13, compound 12 is 1: 1～10: 0～15 with the mol ratio of oxygenant and assistant agent, and described oxygenant is Na
2Cr
2O
7, CrO
3, pyridinium chloro-chromate (PCC), pyridinium dichromate (PDC), KMnO
4, dimethyl sulfoxide (DMSO) (DMSO) or Dai Si-Martin (Dess-Martin) oxygenant; Described assistant agent is NaOAc, KOAc, H
2SO
4, acetate, oxalyl chloride, triethylamine, pyridine or their mixture;
Method E: in non-protonic solvent, after compound 13 and the alkali effect, add oxygenant again, oxidizing reaction is carried out 0.1～24h at-78～60 ℃, obtain compound 14, compound 13 is 1: 1～20: 1～5 with the mol ratio of alkali and oxidising agent, described alkali is hexamethyl two silica-based potassium amides (KHMDS), hexamethyl two silica-based sodium amides (NaHMDS), hexamethyl two silica-based Lithamides (LiHMDS), lithium diisopropylamine (LDA), lithium methide (MeLi), n-Butyl Lithium (n-BuLi), s-butyl lithium (s-BuLi), tert-butyl lithium (t-BuLi), potassium tert.-butoxide (t-BuOK), DBU, pyridine, triethylamine, lutidine or collidine, described oxygenant is an air, oxygen, Davis's reagent (Davis reagent, as
And similar reagents), peroxy propanone, peroxide trifluoroacetone, peroxide Perfluoroacetone, potassium hydrogen persulfate (oxone), Potassium Persulphate, peroxy tert-butyl alcohol or fluoro sulfonic acid fluoride and hydrogen peroxide, described fluoro sulfonic acid fluoride is C
1～18Perfluoroalkyl or Polyfluoroalkyl sulfonic acid fluoride;
Method F: in methyl alcohol, ethanol, acetate, non-protonic solvent or their mixed solvent, assistant agent is arranged or do not have assistant agent in the presence of, compound 14 reacts 0.2～24h with reductive agent down at-78～50 ℃, generate compound 15, compound 14 is 1: 0.25～10: 0～10 with the mol ratio of reductive agent and assistant agent, and described reductive agent is sodium borohydride (NaBH
4), sodium cyanoborohydride (NaBH
3CN), POTASSIUM BOROHYDRIDE (KBH
4), lithium borohydride (LiBH
4), Li-Al hydrogen (LAH), diisobutyl aluminium hydride (DIBALH) or lithium triethylborohydride (LiBHEt
3), described assistant agent is AlCl
3, TiCl
4, BF
3Et
2O or CeCl
37H
2O;
Organic solvent described in the above-mentioned reaction is CH
2Cl
2(DCM), CHCl
3, CCl
4, ethylene dichloride, ether, tetrahydrofuran (THF) (THF), 1,4-diox (dioxane), benzene, toluene, acetonitrile, acetone, the trimethyl carbinol (
tBuOH), H
2O or their mixture; Described non-protonic solvent is CH
2Cl
2, CHCl
3, CCl
4, THF, ether, triethylamine, pyridine or their mixture; Described alcoholic solvent be methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, isopropylcarbinol, sec-butyl alcohol, the trimethyl carbinol (
tBuOH) or their mixture.
Courage steroid compound of the present invention and disaccharides imines ester 18 carry out glycosylation reaction, and then remove protecting group, just can obtain 22-deoxidation-OSW-15 and 17,22-deoxidation-OSW-117:
Major advantage of the present invention has:
1. be basic raw material with natural diosgenin directly, the total recovery of reacting with 15.51% by 10 steps has obtained OSW-1 analogue 22-deoxidation-OSW-1, and the total recovery of reacting with 37.03% by 6 steps has obtained another analogue 17,22-deoxidation-OSW-1.This synthesis strategy has made full use of natural steroid sapogenines diosgenin: utilize its carbon skeleton to synthesize side chain, utilize its functional group further to transform.This is than the more economical rationality of strategy that earlier it is degraded into epiandrosterone and then introduces carbochain.
2. utilize Davis reagent to introduce the 17-hydroxyl, avoid the osmic acid oxidation of using toxicity very big.
Specific implementation method
To help to understand the present invention by following specific implementation method, but not limit content of the present invention.
Embodiment 1 compound 9a's is synthetic
Diosgenin 50.000g is dissolved among 3: 1 the DMF and THF mixed solvent, add 12.08g NaH (＞60%, 2.5eq.), stirring at room 0.5h, and then add the benzyl bromine of 2.3eq., at 100 ℃ of reaction 12h down, reaction finishes.The saturated NaHCO in cooling back
3Cancellation, EA dilution, water EA extraction, the saturated common salt water washing of the organic phase of merging, MgSO
4Drying is filtered, and is spin-dried for, and short column separates, and gets compound 9a 55.39g (91%).
Compound 9a white solid C
34H
48O
3504
1H?NMR(300MHz，CDCl
3)：δ7.36-7.26(m，5H，Ar-H)，5.34(d，J＝3.3Hz，1H，6-H)，4.56(s，2H，Ar-CH
2)，4.40(q，1H，J＝7.2Hz，16-H)，3.45-3.20(m，3H，3-H?and?26-H)，1.03(s，3H，18-CH
3)，0.98(d，3H，J＝7.2Hz，21-CH
3)，0.80(d，3H，J＝3.3Hz，27-CH
3)，0.78(s，3H，19-CH
3)
IR(KBr)υ(cm
-1)：2940，2852，1455，1377，1112，979，736
ESI：505(M
++1)
Embodiment 2 compound 10a's is synthetic
Method one: zinc powder/hydrochloric acid system
20.000g compound 9a is dissolved in ethanol, adds the 600g activated zinc powder, drips the 700ml concentrated hydrochloric acid under reflux, reaction 1.5h, and raw material disappears.Add entry steroidal is separated out, gained solid ethyl alcohol recrystallization gets compound 10a 17.07g (84.7%).
Method two: zinc powder/mercury chloride/hydrochloric acid system
33.000g compound 9a is dissolved in ethanol, adds 1000g activated zinc powder and 6.25g mercury chloride, drips the 700ml concentrated hydrochloric acid under reflux, reaction 2.0h, and raw material disappears.Aftertreatment gets compound 10a28.273g (85.0%) with the description of front.
Compound 10a white solid C
34H
52O
3508
1H?NMR(300MHz，CDCl
3)：δ7.35-7.22(m，5H，Ar-H)，5.34(d，J＝4.8Hz，1H，6-H)，4.56(s，2H，Ar-CH
2)，4.35(m，1H，16-H)，3.48-3.44(m，2H，26-H)，3.37-3.20(m，1H，3-H)，1.02(s，3H，18-CH
3)，0.97(d，3H，J＝6.3Hz，21-CH
3)，0.91(d，3H，J＝6.6Hz，27-CH
3)，0.88(s，3H，19-CH
3)
IR(KBr)υ(cm
-1)：3377，2933，2850，1454，1377，1074，1029，733
ESI：531(M
++23)
HRMS (MALDI), C
34H
52O
3Na
+ 1: calculated value 531.3814
Measured value 531.3809
Embodiment 3 compound 11a's is synthetic
1.411g compound 10a is dissolved in the 5ml dry pyridine, and ice bath adds down 0.798g TsCl (1.5eq.), and room temperature reaction to raw material disappears, and adds the ethyl acetate dilution, and organic phase is with saturated NaCl solution washing four times, MgSO
4Drying is filtered the pressure reducing and steaming solvent.Gained crude product rapid column chromatography separates, and gets compound 11a1.581g (86%).
Compound 11a white solid C
41H
58O
5S 662
1H?NMR(300MHz，CDCl
3)：δ7.79-7.22(m，9H，Ar-H)，5.35(d，J＝4.2Hz，1H，6-H)，4.56(s，2H，Ar-CH
2)，4.31(m，1H，16-H)，3.86(m，2H，26-H)，3.28(m，1H，3-H)，2.45(s，3H，Ar-CH
3)，1.02(s，3H，18-CH
3)，0.95(d，3H，J＝6.9Hz，21-CH
3)，0.89(d，3H，J＝6.3Hz，27-CH
3)，0.88(s，3H，19-CH
3)
IR(KBr)υ(cm
-1)：3566，2928，2852，1598，1464，1377，1354，1190，1174，965，772
MS-MALDI：685(M
++23)
HRMS (MALDI), C
41H
58O
5SNa
+ 1: calculated value 685.3903
Measured value 685.3897
Embodiment 4 compound 12a's is synthetic
40mg compound 11a is dissolved among the 5ml THF, and-78 ℃ add 10mg LAH (4.3eq.) down, reaction 0.5h, and raw material disappears substantially.Add ethyl acetate cancellation reaction, thin up, water EA extraction, the organic phase of merging is with saturated NaCl solution washing, MgSO
4Drying is filtered, the pressure reducing and steaming organic solvent, and rapid column chromatography separates, and gets white solid 12a 27mg (90.8%).
Compound 12a white solid C
34H
52O
2492
1H?NMR(300MHz，CDCl
3)：δ7.35-7.26(m，5H，Ar-H)，5.34(d，J＝4.8Hz，1H，6-H)，4.56(s，2H，Ar-CH
2)，4.35(m，1H，16-H)，3.28(m，1H，3-H)，1.02(s，3H，18-CH
3)，0.99(d，3H，J＝6.9Hz，21-CH
3)，0.89(s，3H，19-CH
3)，0.88(d，6H，J＝7.5Hz，26-CH
3and?27-CH
3)
IR(KBr)υ(cm
-1)：3613，2952，2855，1496，1098，1026，733
MS-MALDI：515(M
++23)
HRMS (MALDI), C
34H
52O
2Na
+ 1: calculated value 515.3868
Measured value 515.3884
Embodiment 5 compound 13a's is synthetic
12a is dissolved in the acetone with the 44mg compound, slowly drips Jones reagent under the condition of ice bath and does not take off until solution colour; Stopped reaction adds Na
2SO
3Saturated solution cancellation reaction, ethyl acetate is fully extracted, and tells organic phase, the saturated common salt water washing, drying concentrates, and rapid column chromatography gets compound 13a 44mg (100%).
Compound 13a white solid C
34H
50O
2490
1H?NMR(300MHz，CDCl
3)：δ7.35-7.26(m，5H，Ar-H)，5.35(d，J＝5.1Hz，1H，6-H)，4.57(s，2H，Ar-CH
2)，3.29(m，1H，3-H)，1.04(s，3H，18-CH
3)，0.98(d，3H，J＝6.6Hz，21-CH
3)，0.88(d，6H，J＝6.9Hz，26-CH
3?and?27-CH
3)，0.84(s，3H，19-CH
3)
IR(KBr)υ(cm
-1)：2954，1732，1467，1365，1101，732
MS-MALDI：513(M
++23)
HRMS (MALDI), C
34H
50O
2Na
+ 1: calculated value 513.3702
Measured value 513.3703
Embodiment 6 compound 14a's is synthetic
Method one: LiHMDS makes alkali
Compound 13a 98mg at room temperature reacts with LiHMDS and makes 16-position enolization, and then at-78 ℃ of Davis reagent that add 1.5eq., TLC tracks to raw material and disappears.The cancellation reaction, ethyl acetate is fully extracted, and tells organic phase, the saturated common salt water washing, drying concentrates, and rapid column chromatography gets compound 14a 15mg (15.2%).
Method two: t-BuOK makes alkali
Compound 13a 28mg is dissolved in anhydrous CCl
4In, the Ac of adding 20eq
2O at room temperature adds the HClO of 0.04eq
4React and make the 16-position generate enol ester, TLC tracks to raw material and disappears.The cancellation reaction, ethyl acetate is fully extracted, and tells organic phase, the saturated common salt water washing, drying concentrates, and the gained crude product is dissolved among the exsiccant THF, and ice-water bath is cooled to 0 ℃.Add 24 milligrams of (0.21mmol) potassium tert.-butoxides fast, stir the 10min postcooling, slowly drip 0.5 milliliter of THF solution of 38 milligrams of (0.142mmol) Davis reagent, stir 30min to-78 ℃.Reaction finishes.Add 50 milligrams of thick silica gel, return to room temperature, filter, mother liquor is spin-dried for, and rapid column chromatography gets compound 14a 19mg (65.7%).
Compound 14a white solid C
34H
50O
3506
1H?NMR(300MHz，CDCl
3)：δ7.35-7.26(m，5H，Ar-H)，5.34(d，J＝5.1Hz，1H，6-H)，4.57(s，2H，Ar-CH
2)，3.30(m，1H，3-H)，1.04(s，3H，18-CH
3)，0.99(d，3H，J＝6.9Hz，21-CH
3)，0.89(d，6H，J＝6.9Hz，26-CH
3?and?27-CH
3)，0.89(s，3H，19-CH
3)
IR(KBr)υ(cm
-1)：3489，2933，1727，1453，1363，1112，997，729
HRMS (MALDI), C
34H
50O
3Na
+ 1: calculated value 529.3661
Measured value 529.3652
Embodiment 7 compound 15a's is synthetic
506mg compound 14a is dissolved among the 25ml exsiccant THF, and-78 ℃ of LAH that add 2.3eq. down, TLC track to raw material and disappear.Add ethyl acetate cancellation reaction, thin up, water EA extraction, the organic phase of merging is with saturated NaCl solution washing, MgSO
4Drying is filtered, the pressure reducing and steaming organic solvent, and rapid column chromatography separates, and gets white solid 15a 483mg (95.1%).
Compound 15a C
34H
52O
3FW 508
1H?NMR(300MHz，CDCl
3)：δ7.35-7.26(m，5H，Ar-H)，5.34(d，J＝4.2Hz，1H，6-H)，4.56(s，2H，Ar-CH
2)，3.96(m，1H，16-H)，3.28(m，1H，3-H)，1.03(s，3H，18-CH
3)，0.96(d，3H，J＝6.3Hz，21-CH
3)，0.91(s，3H，19-CH
3)，0.89(d，6H，J＝6.9Hz，26-CH
3and?27-CH
3)
IR(KBr)υ(cm
-1)：3480，2954，1471，1365，1101，734
MS-MALDI：531(M
++23)
HRMS (MALDI), C
34H
52O
3Na
+ 1: calculated value 531.3803
Measured value 531.3809
Embodiment 8 compound 14b's is synthetic
Compound 13b 127mg is dissolved in anhydrous CCl
4In, the Ac of adding 20eq
2O at room temperature adds the HClO of 0.04eq
4React and make the 16-position generate enol ester, TLC tracks to raw material and disappears.The cancellation reaction, ethyl acetate is fully extracted, and tells organic phase, the saturated common salt water washing, drying concentrates, and the gained crude product is dissolved among the exsiccant THF, ice-water bath is cooled to 0 ℃, add 120 milligrams of (0.21mmol) potassium tert.-butoxides fast, stir the 10min postcooling, slowly drip 0.5 milliliter of THF solution of 190 milligrams of (0.142mmol) Davis reagent to-78 ℃, dropwise the back and stir 30min, reaction finishes.Add 50 milligrams of thick silica gel, slowly return to room temperature, filter, mother liquor is spin-dried for, and rapid column chromatography gets compound 14b 92mg (69.9%).
Compound 14b white solid C
29H
48O
4460
1H?NMR(300MHz，CDCl
3)：δ5.32(d，J＝4.8Hz，1H，6-H)，4.67(2H，s，3-OCH
2OCH
3)，3.35(3H，s，3-OCH
2OCH
3)，3.30(m，1H，3-H)，1.03(s，3H，18-CH
3)，0.98(d，3H，J＝6.9Hz，21-CH
3)，0.89(d，6H，J＝6.9Hz，26-CH
3?and?27-CH
3)，0.87(s，3H，19-CH
3)
IR(KBr)υ(cm
-1)：3464，2935，1725，1466，1374，1105，1043，914
Ultimate analysis: calculated value (%) C75.61 H10.50
Measured value (%) C75.58 H10.53
Embodiment 9 compound 13c's is synthetic
Under-78 ℃, the 3ml DCM solution of 0.16ml DMSO (4.0eq.) is splashed into 0.2ml (COCl)
2In the 4ml DCM solution (4.2eq.), behind the 20min, drip the 8ml DCM solution of 289mg compound 12c (1.0eq.), reaction 20min drips 0.72ml Et again
3N (9.2eq.), reaction removes low temperature behind the 40min, rises to room temperature naturally and continues reaction 20min, and ethyl acetate is diluted, and organic phase is with saturated NaCl solution washing three times, MgSO
4Drying is filtered, the pressure reducing and steaming solvent, and rapid column chromatography separates, and gets compound 13c 259mg (90%).
Compound 13c white solid C
33H
58O
2Si 514
1H?NMR(300MHz，CDCl
3)：δ5.31(d，J＝4.8Hz，1H，6-H)，3.35(m，1H，3-H)，1.04(s，3H，18-CH
3)，0.98(d，3H，J＝6.9Hz，21-CH
3)，0.91(d，6H，J＝6.9Hz，26-CH
3?and?27-CH
3)，0.88(t，9H，J＝7.8Hz)，0.85(s，3H，19-CH
3)，0.54(q，6H，J＝7.8Hz)
IR(KBr)υ(cm
-1)：2961，1737，1469，1366，1121，732
HRMS (MALDI), C
33H
58O
2SiNa
+ 1: calculated value 537.4104
Measured value 537.4112
Embodiment 10 compound 15d's is synthetic
54mg compound 14d is dissolved among the 5ml THF, and-15 ℃ add 57mg (1.3eq.) CeCl down
37H
2O and 27mg (6.0eq.) NaBH
4, rise to room temperature naturally, add water and stir, ethyl acetate extraction, organic phase is with saturated NaCl solution washing, MgSO
4Drying is filtered, and pressure reducing and steaming organic solvent, rapid column chromatography separate (PE: EA=10: 1), get compound 15d 38mg (70.1%).
Compound 15d white foam shape thing C
29H
48O
4FW 460
1H?NMR(300MHz，CDCl
3)：δ5.39(d，J＝4.8Hz，1H，6-H)，4.60(m，1H，3-H)，3.94(m，1H，16-H)，2.04(s，3H，OAc)，1.04(s，3H，18-CH
3)，0.99(d，3H，J＝6.3Hz，21-CH
3)，0.91(s，3H，19-CH
3)，0.85(d，6H，J＝6.9Hz，26-CH
3?and?27-CH
3)
IR(KBr)υ(cm
-1)：3488，2952，1470，732
HRMS (MALDI), C
29H
48O
4Na
+ 1: calculated value 483.3450
Measured value 483.3447
Synthesizing of embodiment 11 compounds 17
Disaccharides imines ester 18 163mg (2.2eq.), compound 12c 41mg (1.0eq.) and 200mg 4 MS stir 15min in the dry DCM of 3ml, (0.005M in DCM 0.05eq.), reacts 1h to ℃ dropping 0.8ml TMSOTf solution then-10.Et
3N cancellation reaction is filtered, and filtrate is spin-dried for, and the crude product of gained compound 16c is dissolved in 2.2ml acetic acid and the 0.9ml water, 75 ℃ of reaction 3h, and raw material disappears, and directly removes solvent under reduced pressure, and rapid column chromatography separates, and gets compound 17 41mg (61.3%).
Compound 17 white foam shape thing C
47H
70O
13FW 842
1H?NMR(300MHz，C
5D
5N)：δ8.25(d，J＝9.0Hz，2H，Ar)，7.01(d，J＝9.0Hz，2H，Ar)，6.16(br?s，1H)，5.84(t，J＝7.5Hz，1H)，5.63(t-like，J＝8.4，7.8Hz，1H)，5.30(brd，J＝4.5Hz，1H)，5.06(d，J＝8.0Hz，1H)，4.75(d，J＝7.2Hz，1H)，4.58(br?s，2H)，4.46(s，1H)，4.35(6H，m)，3.66(s，3H)，2.51(br?d，J＝6.8Hz，2H)，2.40(m，1H)，1.85(s，3H)，1.28(d，J＝6.6Hz，3H)，1.22(s，3H)，0.93(s，3H)，0.84(s，3H)
HRMS (MALDI), C
47H
70O
13Na
+ 1: calculated value 865.4714
Measured value 865.4711
Synthesizing of embodiment 12 compounds 5
(0.675mmol 1.0eq.) is dissolved in the dry DCM of 20ml, adds 0.5g 4A molecular sieve subsequently for disaccharides imines ester 181.274g (2.0eq.) and compound 15a 0.343mg, stirring at room 1 hour is reduced to-20 ℃, adds 0.05eqTMSOTf solution (0.005M in DCM), behind the reaction 1h, Et
3N cancellation reaction is filtered, and filtrate is spin-dried for, and the crude product anhydrous alcohol solution of gained compound 16a adds W-2 type Raney Ni backflow then and removes benzyl, and TLC tracks to 16a and disappears, and filters, and filtrate is spin-dried for, and residue is dissolved in AcOH-THF-H
2(V/V, 8: 8: 1) remove silica-based protecting group in the mixed solvent of O under 45 ℃, directly remove solvent under reduced pressure, and rapid column chromatography separates, and gets compound 5238mg (41.1%).
Compound 5 white foam shape thing C
47H
70O
14FW 858
[α]D
25＝-18.6°(c＝0.40，CH
3OH)
1H?NMR(300MHz，C
5D
5N)：δ8.27(d，J＝9.0Hz，2H，Ar)，7.02(d，J＝9.0Hz，2H，Ar)，6.17(br?s，1H)，5.85(t，J＝7.5Hz，1H)，5.65(t-like，J＝8.4，7.8Hz，1H)，5.32(brd，J＝4.5Hz，1H)，5.08(d，J＝8.0Hz，1H)，4.73(d，J＝7.2Hz，1H)，4.59(br?s，2H)，4.48(s，1H)，4.33-4.15(6H，m)，3.68(s，3H)，2.53(br?d，J＝6.8Hz，2H)，2.42(m，1H)，1.85(s，3H)，1.28(d，J＝6.6Hz，3H)，1.22(s，3H)，0.93(s，3H)，0.81(s，3H)
13C?NMR(75MHz，C
5D
5N)：δ169.35，165.69，164.00，142.11，132.56，121.40，114.23，103.67，102.60，88.13，86.99，80.85，76.31，75.26，71.95，71.49，70.96，68.67，67.10，55.65，50.64，49.56，49.06，47.27，43.67，40.66，37.98，37.08，35.83，34.29，33.42，32.42，30.83，29.40，28.43，25.83，23.24，23.00，21.20，19.76，17.89，14.49，13.36
HRMS (MALDI), C
47H
70O
14Na
+ 1: calculated value 881.4648
Measured value 881.4657.
Claims (9)
1, cholest compound is characterized in that having following structure:
R
1Be H, MOM, Bn, THP, Ac, Bz, Piv, TMS, TES, PMB or TBDPS; R
2Be H or OH; R
3Be H, OH, OMe, OTMS, OAc or and R
4Become carbonyl; R
4Be H or and R
3Become carbonyl; R
5Be H, OMs or OTs;
Work as R
1, R
2And R
4Be H and R
3During for OH, R
5Can not be OH or OTs;
Work as R
1, R
2, R
4And R
5During for H, R
3Can not be OH or OAc;
Work as R
3With R
4Become carbonyl and R
2And R
5During for H, R
1Can not be H, Ac or Bz;
Wherein, MOM is the methoxy methylene radical, and Bn is a benzyl, and THP is a THP trtrahydropyranyl; Ac is an ethanoyl, and Bz is a benzoyl, and Piv is a pivaloyl group, and TMS is trimethyl silicon based; TES is that triethyl is silica-based, and TBDPS is that tert-butyl diphenyl is silica-based, and Ms is a methylsulfonyl, and Ts is a p-toluenesulfonyl.
2, a kind of synthetic method of steroidal compounds as claimed in claim 1 is characterized in that by method A, method A～B, method A～C, method A～D, method A～E or method A～F synthetic:
Method A: in alcoholic solvent, assistant agent is arranged or do not have assistant agent in the presence of, compound 9 stirs 0.2～24h with zinc powder and acid under 0 ℃～reflux temperature, obtain compound 10, the mol ratio of compound 9, zinc powder, acid and assistant agent is 1: 50～250: 50～500: 0～0.5, described acid is organic acid, mineral acid or their mixture, and described assistant agent is HgCl
2, HgBr
2, HgSO
4Perhaps HgO, described alcoholic solvent is methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, isopropylcarbinol, sec-butyl alcohol, the trimethyl carbinol or their mixture;
Method B: under-10～50 ℃ of non-protonic solvent neutralizations, under organic base catalytic, compound 10 generates sulphonate 11 with SULPHURYL CHLORIDE reaction 1～24h, the mol ratio of compound 10, SULPHURYL CHLORIDE and organic bases is 1: 1～5: 0.5～2, and described SULPHURYL CHLORIDE is methylsulfonyl chloride or Tosyl chloride;
Method C: in non-protonic solvent, compound 11 and Li-Al hydrogen generate compound 12 at-78-50 ℃ of reaction 0.2～15h down, and compound 11 is 1: 0.25～10 with the mol ratio of Li-Al hydrogen;
Method D: compound 12 is dissolved in the organic solvent, adds oxygenant, assistant agent is arranged or do not have assistant agent in the presence of, at-78～60 ℃ of reaction 0.1～24h, obtain compound 13, compound 12 is 1: 1～10: 0～15 with the mol ratio of oxygenant and assistant agent, and described oxygenant is Na
2Cr
2O
7, CrO
3, pyridinium chloro-chromate, pyridinium dichromate, KMnO
4, dimethyl sulfoxide (DMSO) or Dai Si-Martin's oxygenant, described assistant agent is NaOAc, KOAc, H
2SO
4, acetate, oxalyl chloride, triethylamine, pyridine or their mixture;
Method E: in non-protonic solvent, after compound 13 and the alkali effect, add oxygenant again, oxidizing reaction is carried out 0.1～24h at-78～60 ℃, obtain compound 14, compound 13 is 1: 1～20: 1～5 with the mol ratio of alkali and oxidising agent, described oxygenant is the mix reagent of air, oxygen, Davis's reagent, peroxy propanone, peroxide trifluoroacetone, peroxide Perfluoroacetone, potassium hydrogen persulfate, Potassium Persulphate, peroxy tert-butyl alcohol or fluoro sulfonic acid fluoride and hydrogen peroxide, and described fluoro sulfonic acid fluoride is C
1～18Perfluoroalkyl or Polyfluoroalkyl sulfonic acid fluoride;
Method F: in methyl alcohol, ethanol, acetate, non-protonic solvent or their mixed solvent, assistant agent is arranged or do not have assistant agent in the presence of, compound 14 reacts 0.2～24h with reductive agent down at-78～50 ℃, generate compound 15, compound 14 is 1: 0.25～10: 0～10 with the mol ratio of reductive agent and assistant agent, and described assistant agent is AlCl
3, TiCl
4, BF
3Et
2O or CeCl
37H
2O;
The structural formula of described compound 9～15 is as follows:
R wherein
1Definition according to claim 1, R
6Be methylsulfonyl or p-toluenesulfonyl.
3, the synthetic method of steroidal compounds as claimed in claim 2 is characterized in that described organic bases is 1,8-diazabicylo [5,4,0] 11-7-alkene, pyridine, 4-Dimethylamino pyridine, bipyridine, lutidine, trimethylpyridine or have C
1～18The primary amine of alkyl, secondary amine or tertiary amine.
4, the synthetic method of steroidal compounds as claimed in claim 2, it is characterized in that described alkali is hexamethyl two silica-based potassium amides, hexamethyl two silica-based sodium amides, hexamethyl two silica-based Lithamides, lithium diisopropylamine, lithium methide, n-Butyl Lithium, s-butyl lithium, tert-butyl lithium, potassium tert.-butoxide, 1,8-diazabicylo [5,4,0] 11-7-alkene, pyridine, triethylamine, lutidine or trimethylpyridine.
5, the synthetic method of steroidal compounds as claimed in claim 2 is characterized in that described reductive agent is sodium borohydride, sodium cyanoborohydride, POTASSIUM BOROHYDRIDE, lithium borohydride, Li-Al hydrogen, diisobutyl aluminium hydride or lithium triethylborohydride.
6, the synthetic method of steroidal compounds as claimed in claim 2 is characterized in that the organic solvent described in the method D is CH
2Cl
2, CHCl
3, CCl
4, ethylene dichloride, ether, tetrahydrofuran (THF), 1,4-diox, benzene, toluene, acetonitrile, acetone, the trimethyl carbinol, H
2O or their mixture.
7, the synthetic method of steroidal compounds as claimed in claim 2 is characterized in that described non-protonic solvent is CH
2Cl
2, CHCl
3, CCl
4, THF, ether, triethylamine, pyridine or their mixture.
8, the synthetic method of steroidal compounds as claimed in claim 2 is characterized in that described acid is acetate, trifluoroacetic acid, phenylformic acid, tosic acid, camphorsulfonic acid, HCl, H
2SO
4Perhaps their mixture.
9, a kind of purposes of steroidal compounds as claimed in claim 1 is characterized in that being used for synthetic 22-deoxidation-OSW-1 or 17 with following structural formula, 22-deoxidation-OSW-1:
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101220073B (en) * | 2007-12-28 | 2010-12-15 | 中山大学 | Synthesis of polyhydroxy ocean steroid (25R)-5 alpha-cholesteric-2 beta,3 alpha,26-triol |
| WO2015158163A1 (en) * | 2014-04-14 | 2015-10-22 | 四川京华创生物科技有限公司 | Cyclopentanoperhydrophenanthrene framework compounds and preparation method therefor |
| CN114989102A (en) * | 2021-12-24 | 2022-09-02 | 成都硕德药业有限公司 | Preparation method of oxazepam |
| CN115555034A (en) * | 2022-10-17 | 2023-01-03 | 湖南科瑞生物制药股份有限公司 | Composite catalyst for converting carbonyl into methylene and preparation method for efficiently catalyzing cholesterol synthesis by using composite catalyst |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1221564C (en) * | 2002-11-05 | 2005-10-05 | 中国科学院上海有机化学研究所 | Steride, its systhesis method and use |
-
2006
- 2006-03-24 CN CNB2006100250500A patent/CN100408593C/en not_active Expired - Fee Related
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101220073B (en) * | 2007-12-28 | 2010-12-15 | 中山大学 | Synthesis of polyhydroxy ocean steroid (25R)-5 alpha-cholesteric-2 beta,3 alpha,26-triol |
| WO2015158163A1 (en) * | 2014-04-14 | 2015-10-22 | 四川京华创生物科技有限公司 | Cyclopentanoperhydrophenanthrene framework compounds and preparation method therefor |
| US10550147B2 (en) | 2014-04-14 | 2020-02-04 | Sichuan Jinghuachuang Biotechnology Corporation | Cyclopentanoperhydrophenanthrene framework compounds and preparation method therefor |
| CN114989102A (en) * | 2021-12-24 | 2022-09-02 | 成都硕德药业有限公司 | Preparation method of oxazepam |
| CN114989102B (en) * | 2021-12-24 | 2024-01-09 | 成都硕德药业有限公司 | Preparation method of oxazepam |
| CN115555034A (en) * | 2022-10-17 | 2023-01-03 | 湖南科瑞生物制药股份有限公司 | Composite catalyst for converting carbonyl into methylene and preparation method for efficiently catalyzing cholesterol synthesis by using composite catalyst |
| CN115555034B (en) * | 2022-10-17 | 2023-08-18 | 湖南科瑞生物制药股份有限公司 | Composite catalyst for converting carbonyl into methylene and preparation method for efficiently catalyzing synthesis of cholesterol by composite catalyst |
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