CN1416875A - 17-hydroxy C27 steroid compound and its synthesis and use - Google Patents
17-hydroxy C27 steroid compound and its synthesis and use Download PDFInfo
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Abstract
The present invention is one kind of 17-hydroxy C27 steroid compound and its synthesis and use. The synthesis process of the present invention is simple and suitable for industrial production in synthesizing pennogenin as well as dihydro pennogenin and OSW-1 aglycone analog.
Description
Technical field
The present invention relates to the steroidal compounds of a class formation novelty, relate to the synthetic method of this compounds, with and purposes in synthetic pennogenin and analog and OSW-1 glycoside unit analog.
Technical background
Steroidal compounds with 17-hydroxyl all has unique biological activity and medical value, as marine natural products Cephalostatine (Cephalostatine) (referring to J.Chem.Soc., Chem..Commun., 1988,865; Ibid, 1988,1440), natural product OSW-1 Orsaponin (OSW-1) is (referring to Bioorg.﹠amp; Med.Chem.Lett., 1997,7,633) and the inclined to one side promise Saponin in YUNNAN BAIYAO and the Sichuan BAIYAO series of products.Pennogenin (Pennogenin) is at first separated from Trillium tschonoskii Maxim (trillium) by R.E.Marker etc. and obtains (referring to J.Arm.Chem.Soc., 1943,65,1248), found afterwards all to contain this Saponin in many Liliaceaes (Liliaceae) plant, the content in Paris Linnaeus(Paris L.) (Paris) plant is more considerable.The main plant resource of famous traditional Chinese medicines-YUNNAN BAIYAO series of products all is a paris plant.The Rhizoma Paridis medicinal history is long, has effects such as heat-clearing and toxic substances removing, reducing swelling and alleviating pain, the arresting convulsion of cool liver, hemostasis heart tonifying, antifertility, antimicrobial (referring to pharmaceutical analysis magazine 1997,17,153; CN 85108520A 16, Jul, 1986; Yakugaku Zasshi, 1982,102,495; China Medicine University's journal, 1989,20,251), pharmaceutical research shows that steroid saponin is its active component, wherein the potato Saponin and partially the promise Saponin be main existence form, in recent years studies show that the promise Saponin is that its main active is (referring to the pharmaceutical analysis magazine partially, 1991,11,90).The content of Pennogenin in Wang Qiang etc. have utilized tlc scanning determination nine kinds of paris plants only is: trace-0.38% (referring to pharmaceutical analysis magazine, 1991,11,90).Because market is to the continuous increase of YUNNAN BAIYAO series of products demand, the excavation amount of required wild plant is also increasing year by year, the scarcity that a large amount of excavation wild plants have not only aggravated the required plant resourceses of YUNNAN BAIYAO series of products, also caused serious vegetation deterioration, synthetic Pennogenin will reduce production YUNNAN BAIYAO series of products to keeping the pressure that ecological balance produces.Potato platymiscium growth cycle is short, the output height, be convenient to the scale plantation, utilize the potato ruscogenin (Diosgenin) of high yield to synthesize the utilization fully rationally that Pennogenin helps resource, do not see bibliographical information as yet from the method for the synthetic Pennogenin of Diosgenin.
From sisalagenin (Tigogenin), adopt similar method, we have synthesized the analog dihydro pennogenin (Dihydropennogenin) of Pennogenin first.
Summary of the invention
The purpose of this invention is to provide a class steroidal compounds.
Another object of the present invention provides the method for synthetic above-mentioned steroidal compounds.
Purpose of the present invention also provides a kind of purposes of above-mentioned steroidal compounds, and these chemical compounds are important intermediate of synthetic pennogenin and analog and their glucoside, also is the important intermediate of synthetic OSW-1 and glycoside unit analog thereof.
The structure of steroidal compounds of the present invention is as follows:
R
1=H, OH, R
2=H, OH, SPh, perhaps R
1And R
2For ehter bond or for singly-bound becomes 16, the two keys of 17-, R
3=H, OH, SPh, S (CH
2)
nSAc, perhaps R
2And R
3Become carbonyl or S (CH
2)
nS, n=2,3 etc.; R
4=OH, OAc, OMs, OTs, OTMS, OTES, OTBS, OTBDPS, OTHP or X; R
5=H, OH, OAc, OMs, OTs, OTMS, OTES, OTBS, OTBDPS, OTHP or X.
In other words, work as R
1When=H, OH, R
2=H, OH, SPh, R
3=H, OH, SPh, S (CH
2)
nSAc, perhaps R
2And R
3Become carbonyl or S (CH
2)
nS; Work as R
2When=H, OH, SPh, R
1=H, OH, R
3=H, OH, SPh, S (CH
2)
nSAc; Work as R
3When=H, OH, SPh, R
1=H, OH, R
2=H, OH, SPh, perhaps R
1And R
2For ehter bond or for singly-bound becomes 16, the two keys of 17-.
Wherein, SPh is a thiophenyl, and Ac is an acetyl group, and Ms is a mesyl; Ts is a p-toluenesulfonyl, and TMS is trimethyl silicon based, and TES is that triethyl group is silica-based, and TBS is that tert-butyl group dimethyl is silica-based; TBDPS is that tert-butyl diphenyl is silica-based, and THP is a THP trtrahydropyranyl, and X is a halogen.
The route of synthetic Pennogenin of the present invention and Dihydropennogenin is as follows:
Chemical compound 1a, 1b and 1c reference literature method preparation (referring to Tetra.Lett., 1994,35,935).
(1). in organic solvent, chemical compound 1 and mercaptan and lewis acid 0-50 ℃ of reaction 1-4 hour, add acetic anhydride, react 5-180 minute, obtain chemical compound 2; Chemical compound 1 is 1 with mercaptan, acetic anhydride and lewis acidic mol ratio: 1-5: 10-50: 1-2; Lewis acid is aluminum chloride (AlCl
3), boron trifluoride diethyl etherate (BF
3Et
2O) or titanium tetrachloride (TiCl
4); Solvent is non-protonic solvent or acetic acid.
(2). in polar solvent, chemical compound 2 and Raney Ni (Raney Ni) backflow 0.5-5 hour obtain chemical compound 3; Every mM chemical compound 2 usefulness 1-3 restrain Raney Ni; Raney Ni is W-2 type or W-6 type etc.
(3). in non-protonic solvent, chemical compound 3 and Osmic acid. (OsO
4)-78-50 ℃ of reaction 5-15 hour, feed excessive H then
2S gets chemical compound 4; Chemical compound 3 and OsO
4Mol ratio be 1: 0.5-1.2.
(4) .-78-0 ℃ to oxalyl chloride ((COCl)
2) solution in drip the solution of dimethyl sulfoxine (DMSO), splash into the solution of chemical compound 4 after 10-30 minute, splash into triethylamine (Et after 10-40 minute
3N), reacted 1-6 hour, get chemical compound 5; Chemical compound 4 with (COCl)
2, DMSO, and Et
3The mol ratio of N is 1: 2-5: 2-5: 4-10; Used solvent is a non-protonic solvent.
(5). in non-protonic solvent, chemical compound 5 and Reducing agent be-78-50 ℃ reaction 5-15 hour, chemical compound 6; Chemical compound 5 is 1 with the mol ratio of Reducing agent: 0.75-10; Reducing agent can be sodium borohydride (NaBH
4), sodium cyanoborohydride (NaBH
3CN), potassium borohydride (KBH
4), lithium borohydride (LiBH
4), Li-Al hydrogen (LiAlH
4) or diisobutyl aluminium hydride (DIBALH).
(6). in protonic solvent, chemical compound 6 and K
2CO
30-50 ℃ of reaction 5-20 hour, add excessive dense HCl then, reacted 5-30 minute, obtain chemical compound 7; Chemical compound 6 and K
2CO
3Mol ratio be 1: 1-5; Protonic solvent is methanol, ethanol or water.
(7). in non-protonic solvent, in the chemical compound 7, R
5=OTBDPS and 5, during 6-pair of key, the mol ratio of this chemical compound and tetrabutyl ammonium fluoride is 1: 1-3 backflow 1-5 hour, gets R
5=OH and 5, the chemical compound 7 of the two keys of 6-, TBDPS is that tert-butyl diphenyl is silica-based;
(8). in non-protonic solvent, chemical compound 3 reacted 1-15 hour at 0-50 ℃ with metachloroperbenzoic acid (mCPBA), obtained chemical compound 8; Chemical compound 3 is 1 with the mol ratio of mCPBA: 1-5.
Non-protonic solvent described in the above-mentioned reaction is CH
2Cl
2, CHCl
3, CCl
4, oxolane (THF) or ether; Described polar solvent is water, acetone, methanol, ethanol, chloroform, dichloromethane or acetonitrile.
Major advantage of the present invention has:
1. be base stock directly, finished the complete synthesis of natural product Pennogenin first by the reaction of 12 steps with natural diosgenin.
2. be base stock with natural sisalagenin, synthesized the analog Dihydropennogenin of Pennogenin by the reaction of 9 steps.
3. obtain the enol thioether by the thio ketal ization open loop and make up 16, the two keys of 17-are committed steps of the present invention, and the method for fractional steps and the one kettle way of the present invention's development all can be realized this conversion.
4. the analog (chemical compound 6a and 6b) that has synthesized OSW-1 glycoside unit first.
5. chemical compound 1a, 1b, 2a, 2b, 3a, 3b, 4a, 4b, 5a, 5b, 8a and 8b have the basic framework of OSW-1 glycoside unit, they all are the important intermediate of the analog of synthetic OSW-1 and glycoside unit thereof, the invention provides the flexible multi-purpose method of a kind of synthetic OSW-1 and glycoside thereof unit analog.
Specific implementation method
To help to understand the present invention by following specific implementation method, but not limit content of the present invention.Embodiment 13 β-tert-butyl diphenyl siloxy-16-(acetyl group-1,2-ethylene dithiol base)-26-acetoxyl group-gallbladder
Synthesizing of gonane-5 (6), 16 (17)-diene-22-ketone (2b)
Chemical compound 1b 97mg is dissolved in 1ml CH
2Cl
2, add 23ul HSCH
2CH
2SH, Dropwise 35 ulBF then
3Et
2O behind the room temperature reaction 2h, adds 0.2ml Ac
2O, reaction 30min, reaction finishes.Add saturated NaHCO
3Solution adds solid NaHCO then
3Do not emerge to there being bubble, ethyl acetate extraction, organic facies is used saturated NaHCO respectively
3Solution and saturated NaCl solution washing, MgSO
4Drying is filtered, the pressure reducing and steaming solvent, and rapid column chromatography separates, and gets colorless oil 67mg (59.2%).C
49H
68O
5S
2Si; 828; [α]
D 20=+45 ° of (C=0.055, CHCl
3);
1H-NMR:7.68 and 7.35 (10H, m, Ph), 5.14 (1H, d, J=4.5Hz, 6-H), 3.88 (2H, d, J=6.0Hz, 26-H), 3.64 (1H, q, J=6.9Hz, 20-H), 3.51 (1H, m, 3-H), 2.95 and 2.78 (4H, m, SCH
2CH
2S), 2.32 (3H, s, SAc), 2.03 (3H, s, OAc), 1.21 (3H, d, J=6.9Hz, 21-Me), 1.05 (9H, s, Bu), 1.00 (3H, s, 19-Me), 0.95 (3H, s, 18-Me), 0.89 (3H, d, J=6.3Hz, 27-Me); MS (EI): 829 (M
++ 1,1.8%) 693 (M,
+-136,2.6%) 672 (M,
+-157,100%) 636 (693-57,19.9%); IR:1738,1714,1696. embodiment, 23 β-tert-butyl diphenyl siloxy-26-acetoxyl group-cholestane-5 (6), 16 (17)-diene-22-ketone
Synthesizing (3b)
800mg2b is dissolved among the anhydrous EtOH of 100ml, adds the about 2.5g of W-2 type RaneyNi, backflow 1h, raw material disappears, and diatomite filtration, residue are with anhydrous EtOH thorough washing, and filtrate is spin-dried for, and the rapid column chromatography separation must colorless oil 608mg (90.7%).C
45H
62O
4Si; FW 694;
1H-NMR:7.68 and 7.35 (10H, m, Ph), 5.34 (1H, br s, 16H), 5.14 (1H, d, J=5.4Hz, 6-H), 3.88 (2H, m, 26-H), 3.53 (1H, m, 3-H), 3.18 (1H, q, J=6.6Hz, 20-H), 2.04 (3H, s, OAc), 1.15 (3H, d, J=6.9Hz, 21-Me), 1.06 (9H, s, Bu), 1.02 (3H, s, 19-Me), 0.92 (3H, d, J=6.3Hz, 27-Me), 0.81 (3H, s, 18-Me); MS (EI): 637 (M
+-57,47.1%) 597 (M,
+-97,11.4%); IR:1741,1715. embodiment, 3 16 α, 17 alpha-dihydroxy-s-3 β-tert-butyl diphenyl siloxy-26-acetoxyl group-cholestane
Synthesizing of-5 (6)-alkene-22-ketone (4b)
1.337g 3b is dissolved in 45ml ether and the 1.5ml pyridine, and-78 ℃ add 1.2eq OsO
4, rise to room temperature naturally, add CH
2Cl
2Make the solid dissolving, logical H
2S gas decomposes osmate, diatomite filtration, residue CH
2Cl
2Thorough washing, filtrate is spin-dried for, and rapid column chromatography separates, and gets white solid 703mg (50.1%).C
45H
64O
6Si; FW 728; [α]
D 20=-36 ° of (C=0.055, CHCl
3);
1H-NMR:7.68 and 7.35 (10H, m, Ph), 5.11 (1H, d, J=5.1Hz, 6-H), 4.11 (1H.m.16H), 3.90 (2H, m, 26-H), 3.53 (1H, m, 3-H), 2.89 (1H, q, J=7.2Hz, 20-H), 2.05 (3H, s, OAc), 1.17 (3H, d, J=6.6Hz, 21-Me), 1.05 (9H, s, Bu), 0.97 (3H, s, 19-Me), 0.94 (3H, d, J=6.6Hz, 27-Me), 0.78 (3H, s, 18-Me); MS (EI): 669 (M
+-59,6.3%) 486 (M,
+-242,18.0%) 485 (M,
+-243,46.1%); IR:3457,1739,1697. embodiment, 4 17 Alpha-hydroxies-3 β-tert-butyl diphenyl siloxy-26-acetoxyl group-cholestane-5 (6)-alkene
-16,22-diketone (5b) synthetic
Under-78 ℃, the 8ml CH of 0.26ml dimethyl sulfoxide (DMSO)
2Cl
2Solution splashes into 0.31ml (COCl)
28ml CH
2Cl
2In the solution, drip the 18ml CH of 664mg chemical compound 4b behind the 15min
2Cl
2Solution, reaction 20min drips 1.0ml Et again
3N is warming up to-20 ℃ naturally, removes ice bath and rise to room temperature naturally, reacts 1 hour, and ethyl acetate is diluted, and organic facies is with saturated NaCl solution washing three times, MgSO
4Drying is filtered, the pressure reducing and steaming solvent, and rapid column chromatography separates, and reclaims raw material 93mg, gets white solid 541mg (81.7%, 95%based on reacted 4b).C
45H
62O
6Si; FW 726; [α]
D 20=-111.3 ° of (C=0.142, CHCl
3);
1H-NMR:7.68 and 7.35 (10H, m, Ph), 5.12 (1H, d, J=7.5Hz, 6-H), (3.95 2H, d, J=6.0Hz 26-H), 3.54 (1H, m, 3-H), 2.67 (1H, q, J=7.5Hz, 20-H), 2.05 (3H, s, OAc), 1.13 (3H, d, J=7.2Hz, 21-Me), 1.05 (9H, s, Bu), 1.00 (3H, s, 19-Me), 0.97 (3H, d, J=6.6Hz, 27-Me), 0.75 (3H, s, 18-Me); MS (EI): 669 (M
+-57,25.2%), 651 (669-18,2.7%), 483 (M
+-243,23.9%); IR:1741,1696. embodiment, 5 16 β, 17 alpha-dihydroxy-s-3 β-tert-butyl diphenyl siloxy-26-acetoxyl group-cholestane
Synthesizing of-5 (6)-alkene-22-ketone (6b)
53mg 5b is dissolved among the 5ml THF, and-78 ℃ add 39mg CeCl down
37H
2O and 28mgNaBH
4, rise to room temperature naturally, add water and stir, ethyl acetate extraction, organic facies 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 32mg (60.2%).C
45H
64O
6Si；FW?728；
1H-NMR：7.68?and?7.35(10H，m，Ph)，5.12(1H，d，J＝5.1Hz，6-H)，4.17(1H.m.16H)， 3.95(2H，m，26-H)，3.55(1H，m，3-H)，2.05(3H，s，OAc)，1.05(9H，s，Bu)，1.00(3H， s，19-Me)，0.95?and?0.93(each?3H，d，J＝6.6Hz?and?J＝7.2Hz，21-and?27-Me)， 0.78(3H，s，18-Me)；MS(EI)：692(M
+-36，25.7％)，653(M
+-75，9.2％)，635(653-18，25.8％)；IR：3466，1740，1700.
Synthesizing of embodiment 63 β-tert-butyl diphenyl siloxy pennogenin (7b)
25mg 6b is dissolved among the 10ml MeOH, adds 16mg K
2CO
3, react to raw material and disappear, drip then as excessive dense HCl, reaction 20min, the pressure reducing and steaming organic solvent adds entry and ethyl acetate, and organic facies 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 22mg (95.9%).C
43H
60O
4Si；FW?668；
1H-NMR：7.68?and?7.35(10H，m，Ph)，5.12(1H，d，J＝4.8Hz，6-H)，3.97(1H，t，J＝7.5Hz， 16H)，3.51(2H，m，26-H)，3.39(1H，t，J＝11.0Hz，3-H)，1.05(9H，s，Bu)，1.00(3H，s， 19-Me)，0.90(3H，d，J＝7.2Hz，21-Me)，0.80(3H，d，J＝6.3Hz，27-Me)，0.79(3H，s， 18-Me)；MS(EI)：668(M
+，1.2％)，651(M
+-17，9.4％)，611(M
+-57，67.1％)；IR：3457，1623.
Synthesizing of embodiment 7 pennogenins (7a)
96mg 7b is dissolved among the 10ml THF, adds 0.22ml TBAF (1M in THF), be back to raw material and disappear saturated NH
4The Cl cancellation, ethyl acetate extraction, organic facies 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 55mg (89%).C
27H
42O
4FW 430;
1H-NMR:5.36 (1H, d, J=5.4Hz, 6-H), 3.98 (1H, t, J=7.5Hz, 16H), 3.52 (2H, m, 26-H), 3.41 (1H, t, J=10.8Hz, 3-H), 1.03 (3H, s, 19-Me), 0.92 (3H, d, J=7.2Hz, 21-Me), 0.82 (3H, s, 18-Me), 0.81 (3H, d, J=6.3Hz, 27-Me); MS (EI): 430 (M
+, 11.2%), 413 (M
+-17,23.5%) 412 (M,
+-18,43.7%); IR:3466,1621. embodiment, 83 β, 26-diacetoxy-16-(acetyl group-1,2-ethylene dithiol base)-cholestane-5 (6), 16 (17)-diene
Synthesizing of-22-ketone (2a)
Chemical compound 1a 154mg is dissolved in 2ml CH
2Cl
2, add 50ul HSCH
2CH
2SH drips 77ulBF then
3Et
2O behind the room temperature reaction 2h, adds 0.45ml Ac
2O, reaction 30min, reaction finishes.Add saturated NaHCO
3Solution adds solid NaHCO then
3Do not emerge to there being bubble, ethyl acetate extraction, organic facies is used saturated NaHCO respectively
3Solution and saturated NaCl solution washing, MgSO
4Drying is filtered, the pressure reducing and steaming solvent, and rapid column chromatography separates, and gets colorless oil 116mg (61.3%).C
35H
52O
6S
2；632；
1H-NMR：5.38(1H，d，J＝4.2Hz，6-H)，4.59(1H，m，3-H)，3.87(2H，d，J＝6.0Hz，26-H)， 3.63(1H，q，J＝6.9Hz，20-H)，2.95?and?2.78(4H，m，SCH
2CH
2S)，2.32(3H，s，SAc)， 2.05?and?2.04(each?3H，s，OAc)，1.21(3H，d，J＝6.9Hz，21-Me)，1.00(3H，s，19-Me)， 0.95(3H，s，18-Me)，0.89(3H，d，J＝6.3Hz，27-Me)；MS(EI)：632(M
+，4.5％)，475(M
+-157，100％)；IR：1736，1714，1695.
Embodiment 93 β, 26-diacetoxy-cholestane-5 (6), 16 (17)-diene-22-ketone (3a) synthetic
475mg 2a is dissolved among the anhydrous EtOH of 50ml, adds the about 1.5g of W-2 type Raney Ni, backflow 1h, raw material disappears, and diatomite filtration, residue are with anhydrous EtOH thorough washing, and filtrate is spin-dried for, and the rapid column chromatography separation must colorless oil 355mg (95%).C
31H
46O
5；498；
1H-NMR：5.38(2H，br?s，6-H，and?16-H)，4.59(1H，m，3-H)，3.87(2H，d，J＝6.0Hz， 26-H)，3.63(1H，q，J＝6.9Hz，20-H)，2.05?and?2.04(each?3H，s，OAc)，1.21(3H，d， J＝6.9Hz，21-Me)，1.00(3H，s，19-Me)，0.95(3H，s，18-Me)，0.89(3H，d，J＝6.3Hz， 27-Me)；MS(EI)：498(M
+，2.8％)，439(M
+-59，50.6％)；IR：1714，1695.
Embodiment 10 3 β, 26-diacetoxy-cholestane-16 (17)-alkene-22-ketone (3c) synthetic
930mg 2c is dissolved among the anhydrous EtOH of 30ml, adds the about 3g of W-2 type Raney Ni, backflow 1h, raw material disappears, and filters, and residue is with anhydrous EtOH thorough washing, and filtrate is spin-dried for, and the rapid column chromatography separation gets white solid 641mg (89.8%).C
31H
48O
5FW 500; Mp 84-86 ℃;
1H-NMR:5.34 (1H, br s, 16-H), 4.69 (1H, m, 3-H), 3.88 (2H, d, J=6.1Hz, 26-H). 3.17 (1H, q, J=6.8Hz, 20-H), 2.05 (3H, s, OAc), 2.02 (3H, s, OAc), 1.15 (3H, d, J=6.9Hz, 21-Me), 0.92 (3H, d, J=6.6Hz, 27-Me), 0.86 (3H, s, 19-Me), 0.81 (3H, s, 18-Me); MS (EI): 500 (M
+, 5.1%), 440 (M
+-60,48.3%); IR:1737,1718,1623; Elementary analysis: value of calculation C%74.36 H%9.66
Measured value C%74.30 H%9.65.
Embodiment 11 3 β, 26-diacetoxy-16 α, 17 α-epoxy-cholestane-22-ketone (8c) synthetic
917mg 3c is dissolved in the 40ml dichloromethane, adds 1.48g mCPBA, room temperature reaction 2h adds the 30ml ethyl acetate in reactant liquor, 2N NaOH washing, and saturated NaCl is washed till neutrality, MgSO
4Drying is filtered, and filtrate is spin-dried for, and rapid column chromatography separates, and gets white solid 944mg (99%).C
31H
48O
6FW 516;
1H-NMR:4.67 (1H, m, 3-H), 3.90 (2H, m, 26-H) .3.14 (1H, s, 16H), 3.10 (1H, q, J=7.0Hz, 20-H), 2.06 (3H, s, OAc), 2.03 (3H, s, OAc), 1.19 (3H, d, J=7.0Hz, 21-Me), 0.93 (3H, d, J=6.7Hz, 27-Me), 0.85 (6H, s, 18-Me and 19-Me);
13C-NMR:210.37,171.21,170.69,73.61,70.01,68.86,59.84,54.56,44.89,44.78,43.61,43.44,38.87,36.65,35.67,33.99,33.89,32.40,32.06,31.64,28.46,27.46,27.29,26.79,21.48,20.97,20.86,16.78,16.21,13.12,12.22; MS (EI): 516 (M
+, 2.1%), 498 (M
+-18,22.7%) 359 (M,
+-157,100%); IR:1732,1702; Elementary analysis: value of calculation C%72.09 H%9.36
Measured value C%72.40 H%9.70.
Claims (8)
1, a kind of steroidal compounds is characterized in that having following structural formula:
R
1=H, OH, R
2=H, OH, SPh, perhaps R
1And R
2For ehter bond or become 16, the two keys of 17-, R
3=H, OH, SPh, S (CH
2)
nSAc, perhaps R
2And R
3Become carbonyl or S (CH
2)
nS, n=2 or 3; R
4=OH, OAc, OMs, OTs, OTMS, OTES, OTBS, OTBDPS, OTHP or X; R
5=H, OH, OAc, OMs, OTs, OTMS, OTES, OTBS, OTBDPS, OTHP or X; Wherein, SPh is a thiophenyl, and Ac is an acetyl group, and Ms is a mesyl; Ts is a p-toluenesulfonyl, and TMS is trimethyl silicon based, and TES is that triethyl group is silica-based, and TBS is that tert-butyl group dimethyl is silica-based; TBDPS is that tert-butyl diphenyl is silica-based, and THP is a THP trtrahydropyranyl, and X is a halogen.
2, a kind of synthetic method of steroidal compounds as claimed in claim 1, it is characterized in that synthesizing (1), (1)-(2), (1)-(3), (1)-(4), (1)-(5), (1)-(6), (1)-(7) or (1)-(2) and (8) by following eight kinds of methods:
(1), in organic solvent, chemical compound 1 and mercaptan and lewis acid 0-50 ℃ of reaction 1-4 hour, add acetic anhydride, react 5-180 minute, obtain chemical compound 2; Chemical compound 1 is 1 with the mol ratio of mercaptan, acetic anhydride and lewis acid: 1-5: 10-50: 1-2;
(2), in polar solvent, chemical compound 2 and Raney Ni backflow 0.5-5 hour obtain chemical compound 3; Every mM chemical compound 2 usefulness 1-3 restrain Raney Ni;
(3), in non-protonic solvent, chemical compound 3 and Osmic acid. feed excessive H then-78-50 ℃ reaction 5-15 hour
2S gets chemical compound 4; Chemical compound 3 is 1 with the mol ratio of Osmic acid.: 0.5-1.2;
(4) ,-78-0 drips the solution of dimethyl sulfoxine ℃ in the solution of oxalyl chloride, splashes into the solution of chemical compound 4 after 10-30 minute, splashes into triethylamine after 10-40 minute, react 1-6 hour, and must chemical compound 5; Chemical compound 4 and oxalyl chloride, dimethyl sulfoxine, and the mol ratio of triethylamine be 1: 2-5: 2-5: 4-10; Used solvent is a non-protonic solvent;
(5), in non-protonic solvent, chemical compound 5 and Reducing agent be-78-50 ℃ reaction 5-15 hour, chemical compound 6; Chemical compound 5 is 1 with the mol ratio of Reducing agent: 0.75-10;
(6), in protonic solvent, chemical compound 6 and K
2CO
30-50 ℃ of reaction 5-20 hour, add excessive dense HCl then, reacted 5-30 minute, get chemical compound 7; Chemical compound 6 and K
2CO
3Mol ratio be 1: 1-5;
(7), in non-protonic solvent, in the chemical compound 7, R
5=OTBDPS and 5, during 6-pair of key, the mol ratio of this chemical compound and tetrabutyl ammonium fluoride is 1: 1-3 backflow 1-5 hour, gets R
5=OH and 5, the chemical compound 7 of the two keys of 6-, TBDPS is that tert-butyl diphenyl is silica-based;
(8), in non-protonic solvent, chemical compound 3 and metachloroperbenzoic acid obtain chemical compound 8 0-50 ℃ of reaction 1-15 hour; Chemical compound 3 is 1 with the mol ratio of metachloroperbenzoic acid: 1-5;
The structure of chemical compound 1-8 is as follows:
Wherein, 5,6-singly-bound or two key, R
5According to claim 1.
3, a kind of synthetic method of steroidal compounds as claimed in claim 2, the described non-protonic solvent of its feature is CH
2Cl
2, CHCl
3, CCl
4, oxolane or ether.
4, a kind of synthetic method of steroidal compounds as claimed in claim 2, the described polar solvent of its feature is water, acetone, methanol, ethanol, chloroform, dichloromethane or acetonitrile.
5, a kind of synthetic method of steroidal compounds as claimed in claim 2 is characterized in that described Raney Ni is W-2 type or W-6 type Raney Ni.
6, a kind of synthetic method of steroidal compounds as claimed in claim 2 is characterized in that described Reducing agent is sodium borohydride, sodium cyanoborohydride, potassium borohydride, lithium borohydride, Li-Al hydrogen or diisobutyl aluminium hydride.
7, a kind of synthetic method of steroidal compounds as claimed in claim 2 is characterized in that described lewis acid is an aluminum chloride, boron trifluoride diethyl etherate or titanium tetrachloride.
8, a kind of purposes of steroidal compounds as claimed in claim 1 is characterized in that being used for synthetic inclined to one side promise Saponin
Unit, dihydro pennogenin or structural formula are: OSW-1 and glycoside unit analog thereof.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005082924A1 (en) * | 2004-01-09 | 2005-09-09 | Shanghai Institute Of Organic Chemistry, Chinese Academy Of Sciences | 23-hetero-analogs of ornithogalum caudatum saponin osw-1, the preparation and use thereof |
| CN100343271C (en) * | 2005-10-28 | 2007-10-17 | 中国科学院上海有机化学研究所 | C27-steroid antitumour medicine |
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| CN1120844C (en) * | 2000-12-22 | 2003-09-10 | 中国科学院上海有机化学研究所 | Lactone compound and its synthesis and use |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2005082924A1 (en) * | 2004-01-09 | 2005-09-09 | Shanghai Institute Of Organic Chemistry, Chinese Academy Of Sciences | 23-hetero-analogs of ornithogalum caudatum saponin osw-1, the preparation and use thereof |
| CN100343271C (en) * | 2005-10-28 | 2007-10-17 | 中国科学院上海有机化学研究所 | C27-steroid antitumour medicine |
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