CN100389123C - Synthesis of 26-bromo-16, 22-dioxy-cholesterol compounds - Google Patents

Abstract

The invention relates to a synthetic method of a class of 26-bromo-16,22-dioxo-cholesterol compounds, that is, under the action of hydrogen bromide-acetic acid solution, the steroidal E/F ketal spiro ring undergoes a ring-opening reaction and 26-bromo, to get 26-bromo-16, 22-dioxo-cholesterol compound, after debromination, cholesteric compound can be obtained, and cholesteric compound can be used to synthesize OSW-1 aglycone and the like things. The reaction process is as follows. The method of the present invention is not only easy to operate, but also suitable for industrial production.

Description

A kind of synthetic method of 26-bromo-16,22-dioxo-cholesterol compounds

technical field

The invention relates to a synthetic method of a class of 26-bromo-16,22-dioxo-cholesterol compounds, that is, the 16-position oxidation product of steroidal saponin or its derivatives is reacted with hydrogen bromide-acetic acid solution to obtain A series of 26-bromo compounds with steroidal E/F ring opening were obtained; after debromination of these compounds, 16,22-dioxo-cholesterol compounds can be obtained, and OSW-1 and its analogues can be further synthesized.

technical background

Tiger eye evergreen saponin (OSW-1) is a saponin with a cholesterol skeleton isolated from the underground bulb of the evergreen ornamental plant Ornithogalum saunderside native to South Africa. It has extremely strong lethality to a variety of malignant tumor cells. It is 10-100 times more effective than several anticancer drugs currently used clinically, such as Mitomycin, Adriamycin, and Taxol. More importantly, although OSW-1 has good activity to various malignant tumor cells, its toxicity to human normal lung cells is very small (IC ₅₀ 1500nM) (seeing Phytochemistry, 1992, 31, 3969 ; Bioorg.&Med.Chem.Lett.1997,7,633), its concrete structure is as follows:

Due to the strong anticancer activity of OSW-1 and its unique chemical structure, and there are few plant resources containing this compound, the chemical synthesis of this type of compound has attracted widespread attention. But most research groups synthesize OSW-1 aglycone (seeing Tetra.Lett.1998,39,1099; J.Org.Chem.1999,64,202; J.Arm.Chem. .Soc.2002,124,6576; CarbohydrateRes.2002,337), and dehydroepiandrosterone is degraded by natural diosgenin (Diosgenin) through six steps of reactions, and the total yield is between 25-50%. Between (see J. Am. Chem. Soc. 1940, 62, 3350; J. Org. Chem. 1956, 21, 520).

People such as Tian Weisheng take diosgenin (diosgenin) as starting raw material, make full use of the complete carbon skeleton of steroidal sapogenin, synthesized tiger eye perennial green saponin (OSW-1) respectively (referring to CN 02145066.8; Tetra.Lett.2003,44 , 9375; CN 200610026473.4) and pennogenin (pennogenin, referring to CN 02150907.7; Chinese Science in China Ser.B Chemistry, 2004,47,142), the synthetic route of the report is as follows:

Synthesis of OSW-1:

As can be seen from the above synthetic route, the synthesis of diketone compound A from diosgenin needs to be first reduced to open the F ring and then oxidized to open the E ring, while the synthesis of diketone compound B only needs to be oxidized to open the E/F ring; and the synthesis of diketone compound A operates It is cumbersome and requires repeated oxidation and separation to complete the conversion. However, the diketone compound B can be obtained from diosgenin with a total yield of more than 70%. In order to synthesize the two natural products OSW-1 and pennogenin more efficiently, Tian Weisheng et al. Two synthetic routes have been integrated to convert the derivative compound D of diketone B, which is easy to prepare in large quantities, into the derivative compound C of diketone A, which is difficult to prepare in large quantities (see CN 200610025917.2):

However, the above route is relatively long, the operation is cumbersome, and the overall yield is low, which is not conducive to the large-scale preparation of compound C.

Tian Weisheng et al also reported the synthesis of 26-bromo-16,22-dioxo-cholesterol compounds, but the efficiency is relatively low (see CN 02150907.7):

26-bromo-16,22-dioxo-cholesterol compound can remove 26-bromo with reference to the method of literature, obtains cholesteric compound A and its analog (referring to J.Med.Chem.1984,27,1690 ; Tetra. Lett. 1994, 35, 935).

The present invention proceeds from the 16-position oxidation product of steroidal saponin or its derivatives, very conveniently prepared 26-bromo-16,22-dioxo-cholesterol compound, and can be further used to synthesize compound A and Its analogs, thereby realizing the accumulation of the amount of key compounds in the synthetic OSW-1 route.

Contents of the invention

The object of the present invention is to provide a synthetic method of a class of 26-bromo-16,22-dioxo-cholesterol compounds.

26-bromo-16 of the present invention, the synthetic method of 22-dioxo-cholesterol compound is as follows:

The 16-position oxidation product 1 of steroidal saponin or its derivatives is dissolved in an aprotic solvent, acetic acid or their mixed solvent, hydrogen bromide-acetic acid solution is added, and the mixture is stirred at -20°C to reflux temperature for 0.5- 24h, obtain 26-bromo-16,22-dioxo-cholesterol compound 2, the molar ratio of compound 1 and hydrogen bromide is 1: 1-10; Described hydrogen bromide-acetic acid solution is to contain 1～ The acetic acid solution of 50% hydrogen bromide; Described aprotic solvent is methylene dichloride, chloroform, carbon tetrachloride, ethylene dichloride, ether, tetrahydrofuran (THF), 1,4-dioxane ( dioxane), benzene, toluene, acetonitrile or their mixed solvents;

The structural formulas of the compounds 1 and 2 are as follows:

代表朝上或者朝下；R¹为H、OH、OMOM、OTHP、OTr、OAc、OBz、OPiv、OTES、OTBS、OTBDPS或者与R²成羰基；R²为H、OH、OMOM、OTHP、OTr、OAc、OBz、OPiv、OTES、OTBS、OTBDPS或者与R¹成羰基；R³为H或者C_1～4的烃基；R⁴为OH、OMOM、OBn、OPMB、OTHP、OTr、OAc、OBz、OPiv、OTMS、OTES、OTBS或者OTBDPS；R⁵为H、OH、OMOM、OBn、OPMB、OTHP、OTr、OAc、OBz、OPiv、OTMS、OTES、OTBS或者OTBDPS；R⁶为H、OH、OAc、OTMS、X或者与R⁷成5，6-双键或5，6-环氧；R⁷为H、OH、OAc、OTMS、X或者与R⁶成5，6-双键或5，6-环氧；

Represents up or down; R ¹ is H, OH, OMOM, OTHP, OTr, OAc, OBz, OPiv, OTES, OTBS, OTBDPS or carbonyl with R ² ; R ² is H, OH, OMOM, OTHP, OTr , OAc, OBz, OPiv, OTES, OTBS, OTBDPS or carbonyl with R ¹ ; R ³ is H or C _1-4 hydrocarbon group; R ⁴ is OH, OMOM, OBn, OPMB, OTHP, OTr, OAc, OBz, OPiv, OTMS, OTES, OTBS or OTBDPS; R ⁵ is H, OH, OMOM, OBn, OPMB, OTHP, OTr, OAc, OBz, OPiv, OTMS, OTES, OTBS or OTBDPS; R ⁶ is H, OH, OAc, OTMS, X or form 5,6-double bond or 5,6-epoxy with R ⁷ ; R ⁷ is H, OH, OAc, OTMS, X or form 5,6-double bond or 5,6- with R ⁶ epoxy;

Wherein, MOM is methoxymethylene, Bn is benzyl, PMB is p-methoxybenzyl, THP is tetrahydropyranyl, Tr is trityl, Ac is acetyl, Bz is benzoyl, Piv is pivaloyl, TMS is trimethylsilyl, TES is triethylsilyl, TBS is tert-butyldimethylsilyl, TBDPS is tert-butyldiphenylsilyl, and X is halogen.

Compound 2 can synthesize cholesteric compound A and its analogs (see J.Med.Chem.1984, 27, 1690; Tetra.Lett.1994, 35, 935) according to the method in the literature, thereby realizing the synthesis of OSW-1 route Accumulation of the amount of key compounds in the .

The present invention starts from the 16-position oxidation product of steroidal saponin or its derivatives, and very conveniently prepares 26-bromo-16,22-dioxo-cholesterol compounds, which are not only easy to operate, but also suitable for industrial production. It has great advantages over existing methods. OSW-1 aglycone and its analogs can be conveniently synthesized by referring to the methods in the literature (see CN 02145066.8; CN 200610025917.2; CN 200610026473.4).

Specific implementation method

The following specific implementation methods will help to understand the present invention, but do not limit the content of the present invention.

Compounds 1a, 1d, 1e, 1f, and 1g of the present invention were synthesized by referring to the methods in the literature (see CN 02150907.7; Tetra. Lett. 1994, 35, 935).

Example 1 Synthesis of Compound 1b and 1c

1.861g of compound 1a was dissolved in 50ml of absolute ethanol, 0.411g of NH ₄ Cl (2.6eq.) and 0.966g of zinc powder (5.0eq.) were added, refluxed for 0.5h, the fluorescence point disappeared, and the reaction was good. Celite was filtered, the filter cake was washed with absolute ethanol, the filtrate was spin-dried, and separated by flash column chromatography (PE:EA=40:1-10:1), and the compound 1b0.139g (10.0%) and the compound 1c 1.314 g (89.0%).

Compound 1b: C ₂₉ H ₄₄ O ₄ ; FW 472; mp 150°C;

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 5.39 (1H, d, J=4.8Hz, 6-H), 4.63-4.57 (1H, m, 3-H), 3.61-3.56 (3H, m, 26-H and 16-OH), 1.03 (3H, s, 19-Me), 1.01 (3H, d, J=6.9Hz, 21-Me), 0.83 (3H, d, J=6.3Hz, 27-Me ), 0.76 (3H, s, 18-Me);

MS(EI): 454 (M ⁺ -18, 11.1%), 43 (100%).

Compound 1c: C ₃₁ H ₄₈ O ₅ ; FW 500; mp 145-148°C;

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 5.38 (1H, d, J=4.8Hz, 6-H), 4.62-4.50 (1H, m, 3-H), 3.70-3.36 (4H, m, 26-H and 16-O CH ₂ CH ₃ ), 2.03 (3H, s, OAc), 1.21 (3H, t, J=7.2Hz, 16-OCH ₂ CH ₃ ), 1.03 (3H, s, 19-Me ), 1.01 (3H, d, J=6.6Hz, 21-Me), 0.81 (3H, d, J=7.8Hz, 27-Me), 0.78 (3H, s, 18-Me).

Embodiment 2 The synthesis of compound 2a

Take 0.5g of compound 1a, dissolve it with 5ml CH ₂ Cl ₂ , add 0.2ml 30% hydrogen bromide-acetic acid solution, react at room temperature, follow TLC until the reaction is complete, it takes about 2h, quench with saturated NaHCO ₃ solution, and the aqueous phase Extracted with CH ₂ Cl ₂ , the combined organic phases were washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , filtered, concentrated and the resulting crude product was separated by column chromatography to obtain 0.415 g of compound 2a (yield 76%).

Compound 2a: C ₂₉ H ₄₃ Br ₃ O ₄ ; FW 692;

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 5.50 (1H, t, J = 5.4Hz, 6-H), 4.83 (1H, m, 3-H), 3.43 (2H, d, J = 5.2Hz , 26-H), 2.03 (3H, s, OAc), 1.04 (6H, S, 18, 19-CH ₃ );

IR v: 2946, 1736, 1377, 1242, 1029 cm ^-1 .

Embodiment 3 The synthesis of compound 2b

Method 1: Synthesis of Compound 2b from Compound 1b

0.299g compound 1b was dissolved in 5ml CH ₂ C1 ₂ , added 0.20ml 33% hydrogen bromide-acetic acid solution, reacted at room temperature for 1.5h, the reaction was completed, quenched with saturated NaHCO ₃ solution, the aqueous phase was extracted with CH ₂ Cl ₂ , combined The organic phase was washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , filtered, concentrated and the crude product obtained was separated by column chromatography to obtain 0.314 g of compound 2b (92.8% yield).

Method 2: Synthesis of Compound 2b from Compound 1c

0.316g compound 1c was dissolved in 5ml CH ₂ Cl ₂ , added 0.30ml 33% hydrogen bromide-acetic acid solution, reacted at room temperature for 3.0h, the reaction was completed, quenched with saturated NaHCO ₃ solution, the aqueous phase was extracted with CH ₂ Cl ₂ , combined The organic phase was washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , filtered, concentrated and the crude product obtained was separated by column chromatography to obtain 0.295 g of compound 2b (yield 87.4%).

Compound 2b: C ₂₉ H ₄₃ BrO ₄ ; FW 534;

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 5.38 (1H, t, J = 4.4Hz, 6-H), 4.62 (1H, m, 3-H), 3.45 (2H, d, J = 5.2Hz , 26-H), 2.17 (3H, s, OAc), 1.04 (6H, s, 18, 19-CH ₃ );

MS (ESI): 536 (M ⁺ +2);

IR v: 2960, 1728, 1456, 1375, 1247, 1021cm ^-1 ;

Elemental Analysis Theoretical value C 65.04%, H 8.09%,

Measured values C 65.46%, H 8.42%.

Embodiment 4 The synthesis of compound 2d

Take 0.3g of compound 1d, dissolve it in 10ml CH ₂ Cl ₂ , add 0.22ml 33% hydrogen bromide-acetic acid solution (2.0eq.), react at room temperature, follow TLC until the reaction is complete, it takes about 1.5h, and dissolve it with saturated NaHCO ₃ The solution was quenched, the aqueous phase was extracted with CH ₂ Cl ₂ , the combined organic phases were washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , filtered, and the crude product was concentrated and separated by column chromatography (PE:EA=16:1) , to obtain 0.306 g of compound 2d (yield 89%).

Compound 2d: C ₂₉ H ₄₅ BrO ₄ ; FW 536;

¹ HNMR (CDCl ₃ , 300 MHz) δ: 4.67 (1H, m, 3-H), 3.34 (1H, m, 26-H), 2.77 (1H, m, 20-H), 2.03 (3H, s, OAc), 1.13 (3H, d, J=6.4 Hz, 21-CH ₃ ), 0.91 (3H, d, J=6.8 Hz, 27-CH ₃ ), 0.85 (3H, s, 19-CH ₃ ), 0.77 (3H, s, 18-CH ₃ );

MS (ESI): 538 (M ⁺ +2);

IR v: 2960, 1728, 1020cm ^-1 ;

Elemental Analysis Theoretical value C 64.79%, H 8.44%,

Measured C 64.76%, H 8.49%.

Embodiment 5 The synthesis of compound 2e

0.433g compound 1e was dissolved in 5ml CH ₂ Cl ₂ , added 0.15ml 37% hydrogen bromide-acetic acid solution, reacted at room temperature, followed by TLC until the reaction was complete, quenched with saturated NaHCO ₃ solution, and the aqueous phase was extracted with CH ₂ Cl ₂ , The combined organic phases were washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , filtered, concentrated and the resulting crude product was separated by column chromatography to obtain 0.357 g of compound 2e (yield 75.6%).

Compound 2e: C ₄₃ H ₅₉ BrO ₄ Si; FW 746;

¹ HNMR (CDCl ₃ , 300 MHz) δ: 7.69-7.65 and 7.40-7.36 (10H, m, Ar), 3.49 (1H, m, 3-H), 3.31 (m, 2H, 26-H), 1.06 ( 9H, s, t-Bu), 1.10(d, 3H, J=6.9Hz, 21-H), 0.96(d, 3H, J=5.4Hz, 27-Me), 0.86(s, 3H, 18-Me ), 0.85(s, 3H, 19-Me);

MS (ESI): 748 (M ⁺ +2);

Elemental Analysis Theoretical value C 69.05%, H 7.95%,

Measured values C 68.83%, H 8.07%.

Embodiment 6 The synthesis of compound 2f

Take 0.339g of compound 1f, dissolve it with 5ml CH ₂ Cl ₂ , add 0.35ml 33% hydrogen bromide-acetic acid solution, react at room temperature, follow TLC until the reaction is complete, quench with saturated NaHCO ₃ solution, and use CH ₂ Cl ₂ for the aqueous phase After extraction, the combined organic phases were washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , filtered, concentrated and the resulting crude product was separated by column chromatography to obtain 0.194 g of compound 2f (51.3% yield).

Compound 2f: C ₃₁ H ₅₁ BrO ₆ ; FW 598;

¹ HNMR (CDCl ₃ , 300 MHz) δ: 4.75-4.71 (m, 2H, 12-O CH ₂ OCH ₃ ), 4.68 (s, 2H, 3-O CH ₂ OCH ₃ ), 3.75 (m, 2H, 3 -H, 12-H), 3.37 (s, 3H, 12-OCH ₂ O CH ₃ ), 3.35 (s, 3H, 3-OCH ₂ O CH ₃ ), 3.30 (m, 2H, 26-H), 1.04 (d, J=6.6Hz, 3H, 21-CH ₃ ), 0.96(d, 3H, J=5.4Hz, 27-Me), 0.87(s, 3H, 18-CH ₃ ), 0.85(s, 3H, 19-CH ₃ );

MS (ESI): 600 (M ⁺ +2);

Elemental analysis Theoretical value C 62.09%, H 8.57%,

Measured values C 62.40%, H 8.49%.

Embodiment 7 The synthesis of compound 2g

Take 0.424g of compound 1g, dissolve it with 5ml _CH2Cl2 , add 0.20ml 30% hydrogen bromide-acetic acid solution, react at _room temperature, follow TLC until the reaction is complete, quench with saturated _NaHCO3 solution, and extract the _aqueous phase with _CH2Cl2 , the combined organic phases were washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , filtered, concentrated and the resulting crude product was separated by column chromatography to obtain 0.187 g of compound 2g (yield 40.4%).

Compound 2g: C ₄₁ H ₄₉ BrO ₇ ; FW 732;

¹ HNMR (CDCl ₃ , 300MHz) δ: 8.03-7.46 (10H, m, Ar), 3.99 (m, 2H, 1-H and 3-H), 3.44 (1H, m, 26-H), 3.04 (m , 1H, 6-H), 1.18 (d, 3H, J=6.9Hz, 21-H), 1.00 (3H, s, 19-Me), 0.95 (3H, s, 18-Me), 0.89 (3H, d, J=6.3Hz, 27-Me);

MS (ESI): 734 (M ⁺ +2);

Elemental Analysis Theoretical value C 67.11%, H 6.73%,

Measured C 67.02%, H 6.54%.

Example 8 Synthesis of Compound 3a

Dissolve 200mg of compound 2a in 5ml of ethanol, add 180mg (10.0eq.) of zinc powder and 38mg of NH ₄ Cl (2.5eq.), heat to reflux for 10h, the reaction is complete, filter to remove the solid, spin the ethanol to dryness, and wash the residue with acetic acid Dissolved in ethyl ester, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude reaction product, which was subjected to flash column chromatography to obtain 90 mg of compound 3a (68.3% yield).

Compound 3a: C ₂₉ H ₄₄ O ₄ ; FW 456;

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 5.37 (1H, d, J = 5.1 Hz, 6-H), 4.62 (1H, m, 3-H), 2.04 (3H, s, OAc), 1.06 (3H, d, J = 6.0Hz, 21-Me), 1.05 (3H, s, 19-Me), 0.91 (6H, d, J = 6.0Hz, 26, 27-Me), 0.81 (3H, s, 18-Me);

MS(EI): 441 (M ⁺ -15, 5.4%), 397 (11.5%), 340 (100%);

IR v: 1732, 1712cm ^-1 .

Embodiment 9 The synthesis of compound 3d

Dissolve 1.072g of compound 2d in 50mL of ethanol, add 0.65g (5.0eq) of zinc powder and 0.268g of NH ₄ Cl (2.5eq), heat to reflux for 4h, the reaction is complete, remove the solid by filtration, spin dry the ethanol, and use Dissolved in ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude reaction product, which was subjected to flash column chromatography to obtain 0.805 mg of compound 3d (yield 87.9%).

Compound 3d: C ₂₉ H ₄₆ O ₄ ; FW 458;

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 4.61 (1H, m, 3-H), 2.04 (3H, s, OAc), 1.06 (3H, d, J=6.0Hz, 21-Me), 0.91 (6H, d, J=6.0Hz, 26, 27-Me), 0.85 (3H, s, 19-Me)), 0.79 (3H, s, 18-Me);

Elemental analysis Theoretical value C 75.94%, H 10.11%,

Measured values C 75.82%, H 9.87%.

Example 10 Synthesis of compound 4

Compound 3a 2.290g was dissolved in 35ml HOAc, 1.06ml HSCH ₂ CH ₂ SH (2.5eq.) was added, then 1.3ml BF ₃ ·Et ₂ O (2.0eq.) was added dropwise, reacted at room temperature for 2.5h, and the raw material disappeared. Then 20ml of Ac ₂ O was added, and the mixture immediately changed from white turbidity to orange-red transparency, and the reaction was completed after 20 minutes of reaction. Add saturated NaHCO ₃ solution, then add solid NaHCO ₃ until no bubbles come out, extract with ethyl acetate, wash the organic phase with NaHCO ₃ solution and saturated NaCl solution, dry with MgSO ₄ , filter, evaporate the solvent under reduced pressure, flash column layer Analysis and separation (PE:EA=40:1) yielded 1.830 g (63.5%) of compound 4 as light yellow viscous oil.

Compound 4: C ₃₃ H ₅₀ O ₄ S ₂ ; FW 574; [α]D ²⁸ =2 1.4° (C=0.433, CHCl ₃ );

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 5.40 (1H, d, J = 3.9Hz, 6-H), 4.61 (1H, m, 3-H), 3.68 (1H, q, J = 6.9Hz , 20-H), 2.98 and 2.81 (4H, m, SCH ₂ CH ₂ S), 2.35 (3H, s, SAc), 2.04 (3H, s, OAc), 1.22 (3H, d, J=7.2Hz, 21-Me), 1.05 (3H, s, 19-Me), 0.98 (3H, s, 18-Me), 0.87 (6H, d, J=5.7Hz, 26, 27-Me);

¹³ C-NMR (CDCl ₃ , 75MHz) δ: 210.98, 195.10, 170.51, 153.39, 139.92, 131.03, 122.11, 73.79, 56.49, 50.09, 48.87, 46.84, 38.58, 38.04, 36.74, 36.78, 34.9 31.25, 30.59, 30.07, 29.75, 27.62, 22.43, 22.35, 21.39, 20.42, 19.15, 17.14, 14.34;

MS(EI): 574 (M ⁺ , 1.2%), 475 (M ⁺ -99, 100%);

HRMS ₍ MALDI): _calcd for _C33H50O4S2Na : _597.3040 ; found: 597.3043;

IR v: 1734, 1713, 1696cm ^-1 .

Example 11 Synthesis of compound 5

Dissolve 930mg of compound 4 in 30ml of absolute ethanol, add about 3.5g of W-2 type Raney nickel, react at room temperature for 0.5h, the raw material disappears, filter, the residue is fully washed with absolute ethanol, the filtrate is spin-dried, and flash column chromatography After separation (PE:EA=20:1), 641 mg (90%) of compound 5 was obtained as a white solid.

Compound 5: C ₂₉ H ₄₄ O ₃ ; FW 440;

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 5.37 (2H, br s, 6-H and 16-H), 4.61 (1H, m, 3-H), 3.20 (1H, q, J=6.9Hz , 20-H), 2.04 (3H, s, OAc), 1.16 (3H, d, J = 6.6Hz, 21-Me), 1.06 (3H, s, 19-Me), 0.87 (6H, d, J = 6.0Hz, 26, 27-Me), 0.85 (3H, s, 18-Me);

MS (ESI): 441 (M ⁺ +1, 100%);

IR v: 1735, 1714, 1244 cm ^-1 .

Claims (2)

1. A synthetic method of 26-bromo-16, 22-dioxo-cholesterol compounds is characterized by comprising the following steps:

in an aprotic solvent, acetic acid or a mixed solvent of the aprotic solvent and the acetic acid, stirring a steroid sapogenin 16-site oxidation product 1 and a hydrogen bromide-acetic acid solution at a temperature of-20 ℃ to reflux temperature for 0.5 to 24 hours to obtain a 26-bromo-16, 22-dioxo-cholesterol compound 2, wherein the molar ratio of the compound 1 to the hydrogen bromide is 1: 1-10; the hydrogen bromide-acetic acid solution is an acetic acid solution containing 1-50% by weight of hydrogen bromide;

the structural formulas of the compound 1 and the compound 2 are shown as follows:

wherein,

represents upward or downward; r¹Is H, OH, OMOM, OTHP, OTr, OAc, OBz, OPiv, OTES, OTBS, OTBDPS or with R²To form a carbonyl group; r²Is H, OH, OMOM, OTHP, OTr, OAc, OBz, OPiv, OTES, OTBS, OTBDPS or with R¹To form a carbonyl group; r³Is H or C_1-4A hydrocarbon group of (a); r⁴OH, OMOM, OBn, OPMB, OTHP, OTr, OAc, OBz, OPiv, OTMS, OTES, OTBS or OTBDPS; r⁵H, OH, OMOM, OBn, OPMB, OTHP, OTr, OAc, OBz, OPiv, OTMS, OTES, OTBS or OTBDPS; r⁶Is H, OH, OAc, OTMS, X or with R⁷To form a 5, 6-double bond or a 5, 6-epoxy; r⁷Is H, OH, OAc, OTMS, X or with R⁶To form a 5, 6-double bond or a 5, 6-epoxy;

MOM is methoxymethylene, Bn is benzyl, PMB is p-methoxybenzyl, THP is tetrahydropyranyl, Tr is trityl, Ac is acetyl, Bz is benzoyl, Piv is pivaloyl, TMS is trimethylsilyl, TES is triethylsilyl, TBS is tert-butyldimethylsilyl, TBDPS is tert-butyldiphenylsilyl, and X is halogen.

2. A method according to claim 1, characterised in that the aprotic solvent is dichloromethane, chloroform, carbon tetrachloride, dichloroethane, diethyl ether, tetrahydrofuran, 1, 4-dioxane, benzene, toluene, acetonitrile or mixtures thereof.