CN1834105A - First 22-ketal steroid compound, synthetic process and applications - Google Patents

First 22-ketal steroid compound, synthetic process and applications Download PDF

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CN1834105A
CN1834105A CN 200610025917 CN200610025917A CN1834105A CN 1834105 A CN1834105 A CN 1834105A CN 200610025917 CN200610025917 CN 200610025917 CN 200610025917 A CN200610025917 A CN 200610025917A CN 1834105 A CN1834105 A CN 1834105A
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synthetic
steroidal compounds
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CN100503631C (en
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田伟生
许启海
陈丽君
李伯玉
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Shanghai Institute of Organic Chemistry of CAS
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Shanghai Institute of Organic Chemistry of CAS
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Abstract

This invention relates to a kind of 22-ketal steroid compound with a novel structure, its synthesis method and its application in synthesis of OSW-1 isoflavone. 22-ketal steroid compound is obtained from the key intermediate in the synthesis of Pennogenin and is further converted into key intermediate in the synthesis of natural product OSW-1 isoflavone so that two synthesis routes can be combined. Therefore, these two natural products can be synthesized more efficiently and a new synthesis scheme of OSW-1 isoflavone is proposed. The structure formula of the steroid compound is shown above.

Description

One class 22-ketal steroidal compounds, preparation method and use
Technical field
The present invention relates to 22-ketal steroidal compounds, synthetic method and this compounds purposes in synthetic OSW-1 glucoside unit of a class formation novelty.Utilize the key intermediate in the pennogenin synthetic route to obtain 22-ketal steroidal compounds, further conversion can be synthesized OSW-1 glucoside unit, thereby has realized the unification of two synthetic routes.
Technical background
Have the alpha-hydroxy steroidal compounds of 17-and all have unique biological activity and pharmaceutical use, as marine natural product Cephalostatine (Cephalostatine) (referring to J.Chem.Soc., Chem..Commun., 1988,865; The same, 1988,1440), natural product OSW-1 (OSW-1) is (referring to Bioorg.﹠amp; Med.Chem.Lett., 1997,7,633) and the inclined to one side promise saponin in Yunnan white powder and the Sichuan baiyao series product (referring to pharmaceutical analysis magazine, 1997,17,153; The pharmaceutical analysis magazine, 1991,11,90; China Medicine University's journal, 1989,20,251):
Figure A20061002591700051
People such as Tian Weisheng are starting raw material with diosgenin (diosgenin), have synthesized OSW-1 glucoside unit respectively (referring to CN 02145066.8; Tetra.Lett., 2003,44,9375) and pennogenin (pennogenin is referring to CN02150907.7), the synthetic route of report is as follows:
OSW-1's is synthetic:
Figure A20061002591700061
Pennogenin's is synthetic:
Figure A20061002591700062
By said synthesis route as can be seen, need reduction earlier to open the F ring and then the E ring is opened in oxidation from the synthetic diketone compound A of diosgenin, and synthetic diketone compound B only need oxidation to open the E/F ring; And synthetic diketone compound A operation is comparatively loaded down with trivial details, needs repeated oxidation and separate to transform comparatively fully, and diketone compound B can be from diosgenin with greater than 70% overall yield acquisition; In order to synthesize OSW-1 and two natural products of Pennogenin more efficiently; the inventor wishes two synthetic routes are integrated, and makes full use of the diketone B that is easy to a large amount of preparations, reach this purpose; only need change into the 26-methyl to the 26-oxygen of diketone B gets final product; this target is to realize, generally will change into sulphonate to hydroxyl, and then reduce with Li-Al hydrogen; but 16; the two carbonyls meeting of 22-preferential reaction need be done due care, so at first explored following reaction:
Figure A20061002591700071
Discover the 16-thio ketal ization derivative C and 16 of diketone B, 17-enol sulfide derivative D is difficult to generate 22-ketal product, and diketone B 16, the two key derivative E of 17-can realize this conversion, obtain the 22-ketal compound of a series of novel structures, these compounds can further be converted into 26-methyl product, thereby have realized the unification of two synthetic routes.
Summary of the invention
The 22-ketal steroidal compounds that the purpose of this invention is to provide a class formation novelty.
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 compounds can be used for Synthetic 2 6-methyl steroidal compound, and can further synthesize OSW-1 glucoside unit.
The structure of 22-ketal steroidal compounds of the present invention is as follows:
Represent singly-bound or two key; R 1Be H, MOM, Bn, THP, Tr, Ac, Bz, Piv, TMS, TES, TBS or TBDPS; R 2Be H, MOM, Bn, THP, Tr, Ac, Bz, Piv, TMS, TES, TBS, TBDPS, Ms or Ts; X 1Or X 2Be oxygen or sulphur; N=2～5;
Wherein, MOM is the methoxy methylene radical, and Bn is a benzyl; THP is a THP trtrahydropyranyl, and Tr is a trityl, and Ac is an ethanoyl; Bz is a benzoyl; Piv is a pivaloyl group, and TMS is trimethyl silicon based, and TES is that triethyl is silica-based; TBS is that tertiary butyl dimethyl is silica-based; TBDPS is that tert-butyl diphenyl is silica-based, and Ms is a methylsulfonyl, and Ts is a p-toluenesulfonyl.
22-ketal steroidal compounds of the present invention can further describe and be following structure:
R wherein 1, X 1, X 2Described as defined above with n, R 3Be MOM, Bn, THP, Tr, Ac, Bz, Piv, TMS, TES, TBS or TBDPS; R 4Be Ms or Ts;
22-ketal steroidal compounds of the present invention is synthetic by method (1), method (1)～(2) or method (1)～(3), is used for Synthetic 2 6-methyl steroidal compound by method (4) then:
Figure A20061002591700082
R wherein 1～R 4, X 1, X 2Described as defined above with n;
Method (1): in non-protonic solvent, compound 1, ketal reagent and catalyzer reacted 1-24 hour under 0 ℃～reflux temperature, obtained compound 2; The mol ratio of compound 1, ketal reagent and catalyzer is 1: 1～30: 0.05～5; Described ketal reagent is C 2～5Glycol, two mercaptan or hydroxy thiol, be recommended as ethylene glycol, propylene glycol, dithioglycol or dimercaptopropane; Described catalyzer is AlCl 3, TiCl 4, BF 3Et 2O, trifluoroacetic acid, tosic acid (TsOH), camphorsulfonic acid (CSA), hydrochloric acid, sulfuric acid, HClO 4Or trimethylsilyl trifluoromethanesulfonate (TMSOTf);
Method (2): in solvent, compound 2 removes reagent with hydroxyl protecting group and reacted 0.5-24 hour under-78 ℃～reflux temperature, obtains compound 3; Compound 2 is 1: 1～20 with the mol ratio that hydroxyl protecting group removes reagent; It is sodium bicarbonate, saleratus, yellow soda ash, salt of wormwood, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, hydrochloric acid, sulfuric acid, TsOH, CSA, HF or tetrabutyl ammonium fluoride (TBAF) that described hydroxyl protecting group removes reagent;
Method (3): in non-protonic solvent, under organic base catalytic, compound 3 generated compound 4 with SULPHURYL CHLORIDE in 1～24 hour-10～50 ℃ of reactions, the mol ratio of compound 3, SULPHURYL CHLORIDE and organic bases is 1: 1～5: 0.5～2, 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 (4): in non-protonic solvent, compound 4 reacts 0.2～15h with Li-Al hydrogen (LAH) at-78～50 ℃, generates compound 5, and compound 4 is 1: 0.25～15 with the mol ratio of LAH;
Solvent described in the above-mentioned reaction is 1,4-diox (dioxane), acetonitrile, acetone, H 2O, acetate, non-protonic solvent, alcoholic solvent or their mixture; Described non-protonic solvent is CH 2Cl 2, CHCl 3, CCl 4, tetrahydrofuran (THF) (THF), ether, sherwood oil (PE), normal hexane, benzene, toluene, triethylamine, pyridine, triethyl orthoformate, trimethyl orthoacetate 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.
The operation of reference literature to compound 5 transform (referring to Tetra.Lett., 1998,39,1099; J.Org.Chem., 1999,64,202; Tetra.Lett., 2003,44,9375), the OSW-1 glucoside unit and 5 that just can be protected, 6-dihydro OSW-1 (dihydro-OSW-1) glucoside unit.
The present invention is from the key intermediate of synthesis of natural product pennogenin, obtain the 22-ketal steroidal compounds of a class formation novelty, and further be converted into the key intermediate of synthesis of natural product OSW-1 glucoside unit, thereby realized the unification of two synthetic routes, help more synthetic these two natural products, also provide a new route for OSW-1 glucoside unit synthetic.
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 2a's is synthetic
Figure A20061002591700101
1a is dissolved in 4ml CH with the 26mg compound 2Cl 2The middle 0.35ml HC (OEt) that adds 3(40eq.) and 29ul (CH 2OH) 2(10eq.), drip 10ul BF 3Et 2O (1.5eq.), room temperature reaction 12h, about 50% transforms.Saturated NaHCO 3Solution cancellation reaction, water CH 2Cl 2Extraction, the organic phase of merging is with saturated NaCl solution washing, MgSO 4Drying is filtered, and pressure reducing and steaming solvent, rapid column chromatography separate (PE: EA=20: 1), get compound 2a 11mg (38.9%, the raw material that deduction reclaims calculates 92%).
Compound 2a:C 33H 50O 6FW 542;
(C＝0.84，CHCl 3)；
1H-NMR：5.67(1H，br?s，16-H)，5.40(1H，d，J＝3.9Hz，6-H)，4.66-4.56(1H，m，3-H)，3.98(4H，s，OCH 2CH 2O)，3.95-3.83(2H，m，26-H)，2.46(1H，q，J＝6.9Hz，20-H)，2.05?and?2.04(each?3H，s，OAc)，1.06(3H，s，19-Me)，1.05(3H，d，J＝6.9Hz，21-Me)，0.92(3H，d，J＝6.0Hz，27-Me)，0.82(3H，s，18-Me)；
HRMS(ESI)：Calcd?for?C 33H 50O 6Na：565.3510；Found：565.3500；
IR：2928，1734，1367，1247，1033.
Embodiment 2 compound 3a's is synthetic
Figure A20061002591700103
50mg compound 2a is dissolved among the 10ml MeOH, adds 10mg K 2CO 3(0.8eq.), backflow 10h, raw material disappears.Pressure reducing and steaming organic solvent, rapid column chromatography separate (PE: EA=2: 1), get compound 3a41mg (97.0%).
Compound 3a:C 29H 46O 4FW 458;
1H-NMR：5.67(1H，br?s，16-H)，5.38(1H，d，J＝3.9Hz，6-H)，3.98(4H，s，OCH 2CH 2O)，3.57-3.38(3H，m，3-H?and?26-H)，2.49(1H，q，J＝6.9Hz，20-H)，1.05(3H，s，19-Me)，1.03(3H，d，J＝6.3Hz，21-Me)，0.91(3H，d，J＝6.9Hz，27-Me)，0.82(3H，s，18-Me).
Embodiment 3 compound 4a's is synthetic
Figure A20061002591700111
1.271g compound 3a is dissolved in the 5ml dry pyridine, and ice bath adds down 0.798g TsCl (1.5eq.), react 3 hours, adds ethyl acetate and dilutes, and organic phase is with saturated NaCl solution washing four times, MgSO 4Drying is filtered the pressure reducing and steaming solvent.Rapid column chromatography separates, and gets compound 4a 1.053g (62.0%).Compound 4a:C 36H 52O 6S; FW 612;
1H-NMR：7.79-7.22(m，4H，Ar-H)，5.67(1H，br?s，16-H)，5.36(1H，d，J＝3.9Hz，6-H)，3.98(4H，s，OCH 2CH 2O)，3.86(m，2H，26-H)，3.28(m，1H，3-H)，2.48(1H，q，J＝6.9Hz，20-H)，2.45(s，3H，Ar-CH 3)，1.05(3H，s，19-Me)，1.03(3H，d，J＝6.3Hz，21-Me)，0.95(3H，d，J＝6.9Hz，27-Me)，0.82(3H，s，18-Me).
IR：2928，1419，1367，1247，1174，771.
MS-MALDI：635(M ++23)
Embodiment 4 compound 5a's is synthetic
Figure A20061002591700112
37mg compound 4a 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 5a 24mg (89.8%).
Compound 5a:C 29H 46O 3FW 442;
1H-NMR：5.68(1H，br?d，J＝1.5Hz，16-H)，5.37(1H，d，J＝4.5Hz，6-H)，3.97(4H，br?s，OCH 2CH 2O)，3.58-3.49(1H，m，3-H)，2.49(1H，q，J＝6.9Hz，20-H)，1.05(3H，s，19-Me)，1.02(3H，d，J＝3.9Hz，21-Me)，0.87?and?0.85(each?3H，d，J＝6.6Hz，26，27-Me)，0.82(3H，s，18-Me).
Embodiment 5 compound 2b's is synthetic
962mg compound 1b is dissolved in 8ml HC (OEt) 3And 5ml (CH 2OH) 2In, add 90mgTsOHH 2O (0.34eq.), room temperature reaction 6.5h, triethylamine cancellation reaction.Add saturated NaCl solution, CH 2Cl 2Extraction, organic phase is with saturated NaCl solution washing, MgSO 4Drying is filtered, the pressure reducing and steaming solvent, and rapid column chromatography separates, and gets compound 2b 514mg (50.2%, the raw material that deduction reclaims calculates 91.0%).
Compound 2b:C 47H 66O 5Si; FW 738;
1H-NMR：7.69-7.65and?7.40-7.36(10H，m，Ar)，5.65(1H，br?s，16-H)，5.30(1H，d，J＝3.9Hz，6-H)，3.97(4H，s，OCH 2CH 2O)，3.95-3.87(2H，m，26-H)，3.58-3.47(1H，m，3-H)，2.46(1H，q，J＝6.9Hz，20-H)，2.05(3H，s，OAc)，1.06(9H，s，t-Bu)，1.04(3H，d，J＝3.6Hz，21-H)，1.01(3H，s，19-Me)，0.97(3H，d，J＝6.6Hz，27-H)，0.77(3H，s，18-H)；
Ultimate analysis: calculated value C 76.38, H 9.00;
Measured value C 76.30, H 9.09.
Embodiment 6 compound 4b's is synthetic
148mg compound 3b is dissolved in the 5ml dry pyridine, and ice bath adds down 61mg TsCl (1.5eq.), react 3 hours, adds ethyl acetate and dilutes, and organic phase is with saturated NaCl solution washing four times, MgSO 4Drying is filtered the pressure reducing and steaming solvent.Rapid column chromatography separates, and gets compound 4b 163mg (90.2%).
Compound 4b:C 52H 70O 6SSi; FW 850;
1H-NMR：7.77-7.22(m，14H，Ar-H)，5.67(1H，br?s，16-H)，5.30(1H，d，J＝3.9Hz，6-H)，3.98(4H，s，OCH 2CH 2O)，3.93-3.87(2H，m，26-H)，3.27(1H，m，3-H)，2.47(1H，q，J＝6.9Hz，20-H)，2.45(s，3H，Ar-CH 3)，1.06(9H，s，t-Bu)，1.04(3H，d，J＝3.6Hz，21-H)，1.01(3H，s，19-Me)，0.97(3H，d，J＝6.6Hz，27-H)，0.77(3H，s，18-H)；
MS-MALDI：873(M ++23).
Embodiment 7 compound 5c's is synthetic
Figure A20061002591700132
263mg compound 5a is dissolved among the dry DMF of 2ml, adds 102mg imidazoles (2.5eq.) and 180mg TBSCl (2.0eq.), room temperature reaction 2.5h, raw material disappears.Add entry and ethyl acetate, organic phase is with saturated NaCl solution washing three times, MgSO 4Drying is filtered, and pressure reducing and steaming organic solvent, rapid column chromatography separate (PE: EA=20: 1), get compound 5c 317mg (95.8%).
Compound 5c:C 35H 60O 3Si; FW 556;
1H-NMR：5.67(1H，br?s，16-H)，5.34(1H，d，J＝4.8Hz，6-H)，4.05-3.87(4H，br?s，OCH 2CH 2O)，3.54-3.43(1H，m，3-H)，1.04(3H，s，19-Me)，1.02(3H，d，J＝6.9Hz，21-Me)，0.89(9H，s，t-Bu)，0.87?and?0.85(each?3H，d，J＝6.6Hz，26，27-Me)，0.81(3H，s，18-Me)，0.05(6H，s，Si-Me)；
MS-MALDI：579(M ++23).
Synthesizing of embodiment 8 compounds 6
600mg compound 5c is dissolved in 60ml ether and the 1ml pyridine, and-78 ℃ add 329mg OsO 4(1.2eq.), rise to room temperature naturally, logical H 2S decomposing gas osmate filters residue CH 2Cl 2Thorough washing, filtrate is spin-dried for, and rapid column chromatography separates, and gets compound 6 443mg (69.6%).
Compound 6:C 35H 62O 5Si; FW 590;
1H-NMR：5.35(1H，d，J＝4.8Hz，6-H)，4.28(1H，m，16-H)，4.03-3.87(4H，m，OCH 2CH 2O)，3.51-3.43(1H，m，3-H)，1.04(3H，s，19-Me)，1.02(3H，d，J＝6.9Hz，21-Me)，0.88(9H，s，t-Bu)，0.87and?0.85(each?3H，d，J＝6.6Hz，26，27-Me)，0.81(3H，s，18-Me)，0.05(6H，s，Si-Me)；
MS-MALDI：613(M ++23).
Synthesizing of embodiment 9 compounds 7
Under-78 ℃, the 3ml CH of 0.16ml DMSO (4.0eq.) 2Cl 2Solution splashes into 0.2ml (COCl) 24ml CH (4.2eq.) 2Cl 2In the solution, behind the 20min, drip the 8mlCH of 330mg compound 6 (1.0eq.) 2Cl 2Solution, 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 7295mg (89.7%).
Compound 6:C 35H 60O 5Si; FW 588;
1H-NMR：5.31(1H，d，J＝4.8Hz，6-H)，4.70(1H，s，17-OH)，4.01(4H，m，OCH 2CH 2O)，3.49(1H，m，3-H)，2.75(1H，q，J＝7.5Hz，20-H)，1.03(3H，s，19-Me)，1.01(3H，d，J＝7.8Hz，21-Me)，0.93(3H，s，18-Me)，0.90(15H，brs，26，27-Me?and?t-Bu)，0.05(6H，s，Me-Si)；
MS-MALDI：611(M ++23).
The OSW-1 glucoside unit (compound 8) of embodiment 10 protections synthesizes
69mg compound 7 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 8 white solid 66mg (95.3%).
Compound 8:C 35H 62O 5Si; FW 590;
mp?183-185℃；
1H-NMR：5.29(1H，d，J＝4.8Hz，6-H)，4.04(6H，m，OCH 2CH 2O，16-OH，17-OH)，3.88(1H，m，16-H)，3.49(1H，m，3-H)，2.59(1H，q，J＝7.2Hz，20-H)，1.18(3H，d，J＝7.2Hz，21-Me)，0.99(3H，s，19-Me)，0.89(18H，brs，18，26，27-Me?and?t-Bu)，0.05(6H，s，Me-Si)；
13C-NMR：141.37，121.09，116.45，86.75，81.52，72.53，64.04，62.80，49.59，47.84，47.78，42.71，37.23，36.47，35.84，33.86，33.09，32.73，32.70，32.01，31.87，31.84，28.25，25.90，22.69，22.24，20.63，19.39，18.21，12.50，11.92，-4.63；
MS(EI)：575(M +-15，0.9％)，533(M +-57，6.8％)，485(M +-57-18-15-15，18.9％)；
IR：3545，3472，1076.
Embodiment 11 compound 2d's is synthetic
1d is dissolved in 20ml CH with the 101mg compound 2Cl 2In, add 1.6ml HC (OEt) 3(40eq.) and 133ul (CH 2OH) 2(10eq.), drip 46ul BF 3Et 2O (1.5eq.), room temperature reaction 17h.Saturated NaHCO 3Solution cancellation reaction, water CH 2Cl 2Extraction, the organic phase of merging is with saturated NaCl solution washing, MgSO 4Drying is filtered, and pressure reducing and steaming solvent, rapid column chromatography separate (PE: EA=25: 1), get compound 2d 58mg (52.7%, the raw material that deduction reclaims calculates 98%).
Compound 2d:C 33H 52O 6FW 544;
1H-NMR：5.64(1H，s，16-H)，4.67-4.71(1H，m，3-H)，3.99(4H，s，OCH 2CH 2O)，3.84-3.97(2H，m，26-H)，2.45(1H，q，J＝6.9Hz，20-H)，2.05and?2.05(each?3H，s，OAc)，1.04(3H，d，J＝6.9Hz，21-Me)，0.92(3H，d，J＝6.0Hz，27-Me)，0.86(3H，s，19-Me)，0.82(3H，s，18-Me)；
HRMS(ESI)：Calcd?for?C 33H 52O 6Na：544.3764；Found：544.3760；
IR：2926，1733，1367，1245，1035.
Embodiment 12 compound 2f's is synthetic
Figure A20061002591700162
2e is dissolved in 50ml CH with the 427mg compound 2Cl 2In, add 6mg DMAP (0.5eq) and 517mgTrCl (2eq), drip Et 3N (1.1eq), reflux, reaction 20h, TLC tracks to no raw material, adds the shrend reaction of going out, water CH 2Cl 2Extraction, the organic phase of merging is with saturated NaCl solution washing, MgSO 4Drying is filtered, and pressure reducing and steaming solvent, rapid column chromatography separate (PE: EA=10: 1～5: 1), get compound 2f 430mg (70.4%).
Compound 2f:C 48H 62O 4FW 702;
1H-NMR：7.18-7.44(15H，s，Ar-H)，5.59(1H，s，16-H)，3.93(4H，s，-OCH2CH2O-)，3.59(1H，m，3-H)，2.81-2.91(2H，dt，26-H)，2.41(3H，t，20-H)，0.98，1.00(3H，d，J＝6.0Hz，21-Me)，0.90-0.92(3H，d，J＝6.0Hz，27-Me)，0.84(3H，s，19-Me)，0.70(3H，s，18-Me)；
HRMS(ESI)：Calcd?for?C 48H 62O 4Na：702.4648；Found：702.4645.
Embodiment 13 compound 2g's is synthetic
Figure A20061002591700171
293mg compound 1g is dissolved in the dry CH of 8ml 2Cl 2In, add the 60ul dimercaptopropane, drip 75ul BF then 3Et 2O, room temperature reaction 2.5h, saturated NaHCO 3Solution cancellation reaction, the water ethyl acetate extraction, organic phase 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 compound 2g 94mg (27.2%).
Compound 2g:C 39H 56O 3S 2FW 636;
1H-NMR：5.64(1H，s，16-H)，4.67-4.71(1H，m，3-H)，3.99(4H，s，OCH 2CH 2O)，3.84-3.97(2H，m，26-H)，2.45(1H，q，J＝6.9Hz，20-H)，2.05and?2.05(each?3H，s，OAc)，1.04(3H，d，J＝6.9Hz，21-Me)，0.92(3H，d，J＝6.0Hz，27-Me)，0.86(3H，s，19-Me)，0.82(3H，s，18-Me)；
HRMS(ESI)：Calcd?for?C 39H 56O 3S 2Na：659.3569；Found：659.3566.

Claims (10)

1, a class 22-ketal steroidal compounds is characterized in that having following structure:
Figure A2006100259170002C1
Figure A2006100259170002C2
Represent singly-bound or two key; R 1Be H, MOM, Bn, THP, Tr, Ac, Bz, Piv, TMS, TES, TBS or TBDPS; R 2Be H, MOM, Bn, THP, Tr, Ac, Bz, Piv, TMS, TES, TBS, TBDPS, Ms or Ts; X 1Or X 2Be oxygen or sulphur; N=2～5; Wherein, MOM is the methoxy methylene radical, and Bn is a benzyl; THP is a THP trtrahydropyranyl, and Tr is a trityl, and Ac is an ethanoyl; Bz is a benzoyl; Piv is a pivaloyl group, and TMS is trimethyl silicon based, and TES is that triethyl is silica-based; TBS is that tertiary butyl dimethyl is silica-based; TBDPS is that tert-butyl diphenyl is silica-based, and Ms is a methylsulfonyl, and Ts is a p-toluenesulfonyl.
2, class 22-ketal as claimed in claim 1 steroidal compounds is characterized in that further describing and is following structure:
Figure A2006100259170002C3
R wherein 3Be MOM, Bn, THP, Tr, Ac, Bz, Piv, TMS, TES, TBS or TBDPS; R 4Be Ms or Ts; R 1, X 1, X 2, n, MOM, Bn, THP, Tr, Ac, Bz, Piv, TMS, TES, TBS, TBDPS, Ms and Ts definition according to claim 1.
3, a kind of synthetic method of steroidal compounds as claimed in claim 1 is characterized in that by method (1), method (1)～(2) or method (1)～(3) synthetic:
Method (1): in non-protonic solvent, compound 1, ketal reagent and catalyzer reacted 1-24 hour under 0 ℃～reflux temperature, obtained compound 2; The mol ratio of compound 1, ketal reagent and catalyzer is 1: 1～30: 0.05～5; Described ketal reagent is C 2～5Glycol, two mercaptan or hydroxy thiol, be recommended as ethylene glycol, propylene glycol, dithioglycol or dimercaptopropane;
Method (2): in solvent, compound 2 removes reagent with hydroxyl protecting group and reacted 0.5-24 hour under-78 ℃～reflux temperature, obtains compound 3; Compound 2 is 1: 1～20 with the mol ratio that hydroxyl protecting group removes reagent;
Method (3): in non-protonic solvent, under organic base catalytic, compound 3 generated compound 4 with SULPHURYL CHLORIDE in 1～24 hour-10～50 ℃ of reactions, the mol ratio of compound 3, SULPHURYL CHLORIDE and organic bases is 1: 1～5: 0.5～2, and described SULPHURYL CHLORIDE is methylsulfonyl chloride or Tosyl chloride;
The structural formula of described compound 1～4 is as follows:
Wherein R 1, R 3, R 4, X 1, X 2With the definition of n as described in the claim 2.
4, a kind of synthetic method of steroidal compounds as claimed in claim 3 is characterized in that described catalyzer is AlCl 3, TiCl 4, BF 3Et 2O, trifluoroacetic acid, tosic acid, camphorsulfonic acid, hydrochloric acid, sulfuric acid, HClO 4Or trimethylsilyl trifluoromethanesulfonate.
5, a kind of synthetic method of steroidal compounds as claimed in claim 3 is characterized in that described solvent is 1,4-diox, acetonitrile, acetone, H 2O, acetate, non-protonic solvent, alcoholic solvent or their mixture; Described alcoholic solvent is methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, isopropylcarbinol, sec-butyl alcohol, the trimethyl carbinol or their mixture.
6, a kind of synthetic method of steroidal compounds as claimed in claim 3 is characterized in that described non-protonic solvent is CH 2Cl 2, CHCl 3, CCl 4, tetrahydrofuran (THF), ether, sherwood oil, normal hexane, benzene, toluene, triethylamine, pyridine, triethyl orthoformate, trimethyl orthoacetate or their mixture.
7, a kind of synthetic method of steroidal compounds as claimed in claim 3 is characterized in that it is sodium bicarbonate, saleratus, yellow soda ash, salt of wormwood, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, hydrochloric acid, sulfuric acid, tosic acid, camphorsulfonic acid, HF or tetrabutyl ammonium fluoride that described hydroxyl protecting group removes reagent.
8, a kind of synthetic method of steroidal compounds as claimed in claim 3, it 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.
9, a kind of purposes of steroidal compounds as claimed in claim 1 is characterized in that being used for Synthetic 2 6-methyl steroidal compound and OSW-1 unit and analogue thereof.
10, the purposes of steroidal compounds as claimed in claim 10 is characterized in that by following method Synthetic 2 6-methyl steroidal compound:
In non-protonic solvent, compound 4 reacts 0.2～15h with Li-Al hydrogen at-78～50 ℃, generates the 26-methyl steroidal compound, and compound 4 is 1: 0.25～15 with the mol ratio of Li-Al hydrogen; Described non-protonic solvent is CH 2Cl 2, CHCl 3, CCl 4, tetrahydrofuran (THF), ether, sherwood oil, normal hexane, benzene, toluene or their mixture;
The structural formula of described 26-methyl steroidal compound is as follows:
Figure A2006100259170004C1
Wherein
Figure A2006100259170004C2
R 1, X 1, X 2With the definition of n according to claim 1.
CNB2006100259172A 2006-04-21 2006-04-21 First 22-ketal steroid compound, synthetic process and applications Expired - Fee Related CN100503631C (en)

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