CN1098273C - High-stereoselectivity synthesization of 24R,25- and 24S, 25-dihydroxysteroid - Google Patents

High-stereoselectivity synthesization of 24R,25- and 24S, 25-dihydroxysteroid Download PDF

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CN1098273C
CN1098273C CN99124007A CN99124007A CN1098273C CN 1098273 C CN1098273 C CN 1098273C CN 99124007 A CN99124007 A CN 99124007A CN 99124007 A CN99124007 A CN 99124007A CN 1098273 C CN1098273 C CN 1098273C
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synthetic
alpha
courage steroid
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CN1254716A (en
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周向东
周维善
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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

The present invention relates to a method for synthesizing a 24R, 25- or 24S, 25-dihydric compound by improved, sharpless and asymmetric bi-hydroxylation reaction, wherein R1 or R2 can be methoxy methyl ether groups (MOMO for short), tetrahydropyrans group (THP for short), acetoxyl groups (AcO for short), OCH2CH2O, OH, H, benzoyl groups (PhCOO for short), methanesulfonate (MeSO2 O for short), p-toluenesulfonate (Tso for short), O, tert-butyl dimethyl silicone ether (TBSO for short) and benzyl (Bn for short). R3=alpha- or beta-H, or R3 R4 = double bonds. R4, R5, R6= MOMO, THP, AcO, OCH2CH2O, OH, H, PhCOO, MeSo2O or TsO, O, or R4, R5= O. R6 or R7=MOMO, THP, AcO, OCH2CH2O, OH, H, PhCOO, MeSo2O, TsO, O. R6R7=O. R8, R9=H or OH. The method has the advantages of high reaction speed and high stereoselectivity, and is suitable for industrial production.

Description

The Synthetic 2 4R of highly-solid selectively, 25-and 24S, 25-dihydroxyl steroidal compounds
The present invention relates to improved Sharpless asymmetric dihydroxylation reaction, specifically a kind of from Δ 24The Synthetic 2 4R of-steroidal compounds highly-solid selectively, 25-and 24S, the method for 25-dihydroxyl steroidal compounds.
As everyone knows, the Sharpless asymmetric dihydroxylation reaction has been obtained satisfied result to the asymmetric dihydroxylation of general olefin(e) compound, in the tertiary butanol and water solvent, adds three normal K usually 3Fe (CN) 6, three normal K 2CO 3, monovalent CH 3SO 2NH 2Potassium osmate (K with catalytic amount 2OsO 2(OH) 4) and 1, two (9-O the dihydro-quinidine)-2 ((DHQD) of 4- 2PHAL) or 1, two (9-O dihydro Kui the Buddhist nun)-2 ((DHQ) of 4- 2PHAL), under the room temperature, stir, add olefine reaction to reacting completely.But for steroidal compounds, reaction result is undesirable, its cis-selectivity generally not high (10: 1～96: 4), and long reaction time generally needs 3～6 days.(K.B.Sharpless，Chem.Rev.1994，94，2483～2547；E.J.Corey.Tetrahedron?Lett.1998，39，9351～9354；CA127：34408(1998)：Eur.Pat.Appl.EP?776905)。So people expect to improve stereoselectivity, shorten the Synthetic 2 4R of synthetic method, the especially highly-solid selectively in reaction times, 25-or 24S, the method for 25-dihydroxyl steroidal compounds.
The purpose of this invention is to provide a kind of improved Sharpless asymmetric dihydroxylation reaction, be used for the Synthetic 2 4R of highly-solid selectively, 25-or 24S, 25-dihydroxyl steroidal compounds.
Method of the present invention is in the tertiary butanol and water mixed solvent, Δ 24-steroidal compounds and K 3Fe (CN) 6, K 2CO 3, CH 3SO 2NH 2K with catalytic amount 2OsO 2(OH) 4(DHQD) 2PHAL or (DHQ) 2PHAL reacts to room temperature at 0 ℃, during reaction, adds second kind of solvent, to improve stereoselectivity and to shorten the reaction times.Added second kind of solvent is tetrahydrofuran (THF) (THF), N, dinethylformamide (DMF), glycol dimethyl ether (DME), acetonitrile, t-butyl methyl ether (MBE), ether, isopropyl ether, acetone, butanone, 1,6-dioxane, N, N-dimethyl acetyl ammonia etc.After adding above-mentioned solvent, reacted 10～20 hours, acquisition that can highly-solid selectively has various A, the 24R of B-ring structure, 25-or 24S, 25-dihydroxyl steroidal compounds.
The Δ that is adopted among the present invention 24-steroidal compounds has following structural formula:
Figure C9912400700041
R wherein 1Or R 2=methoxy methyl ether (being called for short MOMO), THP trtrahydropyranyl (being called for short THP), acetoxyl group (being called for short AcO), OCH 2CH 2O, OH, H, benzoyl (being called for short PhCOO), methanesulfonates (is called for short MeSO 2O), p-toluenesulfonic esters (being called for short TsO), tertiary butyl dimethyl-silicon ether (being called for short TBSO), benzyl (being called for short Bn); Or R 1Or R 2=O, R 3=α-or β-H, or R 3R 4=two keys, R 4Or R 5=MOMO, THP, AcO, OCH 2CH 2O, OH, H, PhCOO, MeSO 2O or TsO; Or R 4R 5=O.R 6Or R 7=MOMO, THP, AcO, OCH 2CH 2O, OH, H, PhCOO, MeSO 2O, TsO.Or R 6R 7=O.
When adopting method of the present invention, can be with second kind of above-mentioned dissolution with solvents Δ 24-steroidal compounds joins this solution in the solution of above-mentioned tertiary butanol and water and other reagent again and reacts.
In the method for the invention, Δ 24-steroidal compounds, K 3Fe (CN) 6, K 2CO 3, CH 3SO 2NH 2, K 2OsO 2(OH) 4, (DHQD) 2PHAL or (DHQ) 2The mol ratio of PHAL is 1: 1～5: 1: 1～5: 0.5～3: 0.005～0.01.
In the inventive method, in the mixing solutions of the tertiary butanol and water that adopts, the volume ratio of the trimethyl carbinol and water is 1: 0.5～2.Δ in the reaction 24The amount ratio of-steroidal compounds and tertiary butanol and water is every mole of Δ 24-steroidal compounds adds the mixing solutions of 1～10 liter tertiary butanol and water.
Adopt method of the present invention can obtain the 24R of following structure, 25-or 24S, 25-dihydroxyl steroidal compounds.
R wherein 1Or R 2=methoxy methyl ether (being called for short MOMO), THP trtrahydropyranyl (being called for short THP), acetoxyl group (being called for short AcO), OCH 2CH 2O, OH, H, benzoyl (being called for short PhCOO), methanesulfonates (is called for short MeSO 2O), p-toluenesulfonic esters (being called for short TsO),, tertiary butyl dimethyl-silicon ether (being called for short TBSO), benzyl (being called for short Bn) or R 1R 2=O; R 3=α-or β-H, or R 3R 4=two keys, R 4Or R 5=MOMO, THP, AcO, OCH 2CH 2O, OH, H, PhCOO, MeSO 2O or TsO; Or R 4R 5=O.R 6Or R 7=MOMO, THP, AcO, OCH 2CH 2O, OH, H, PhCOO, MeSO 2O, TsO.Or R 6R 7=O.R 8, R 9=H or OH.In other words, can be the compound of following structure respectively:
As 5 β-3 α, 6 alpha, alpha-dimethyl oxygen ylmethyl-3 α, 6 α, 24R, 25-tetrahydroxy courage steroid, 5 β-3 α, 6 alpha, alpha-dimethyl oxygen ylmethyl-3 α, 6 α, 24S, 25-tetrahydroxy courage steroid, Δ 5,24-3 β-acetoxy-3 β, 24R, 25-trihydroxy--courage steroid, Δ 5-3 β-acetoxy-3 β, 24S, 25-trihydroxy--courage steroid, Δ 5,24Silica-based-3 β of-3 β-(tertiary butyl-dimethyl), 24R, 25-trihydroxy--courage steroid, Δ 5Silica-based-3 β of-3 β-(tertiary butyl-dimethyl), 24S, 25-trihydroxy-courage steroid or the like.The 24R of the high-optical-purity of gained, 25-or 24S, the 24R that 25-dihydroxyl steroidal compounds can be respectively applied for synthetic osteoporosis disease as intermediate, 25-dihydroxyl VD 3, the anti-hypercholesterolemia ester of lxr agonist disease 24S, 25-epoxy cholesterol, 24S-hydroxycholesterol and some Δs 25Antineoplastic natural compoundss such as-24R-or 24S-hydroxycholesterol.
Adopt method of the present invention, Synthetic 2 4R that not only can highly-solid selectively, 25-or 24S, 25-dihydroxyl steroidal compounds, its diastereomeric excess value (de%) is up to 95～100%, and the reaction times also foreshortened to 10～20 hours by 3～6 days, be the method that is suitable for suitability for industrialized production.
Help further to understand the present invention by following examples, but can not limit content of the present invention:
Embodiment 15 β-3 α, 6-methoxymethyl-3 α, 6 α, 24R, 25-tetrahydroxy courage steroid glycol 2
Figure C9912400700061
In the 25ml egg type bottle, add magneton, 495mg (1.5mmol) K 3Fe (CN) 6, 207mg (1.5mmol) K 2CO 3, 48mg (0.5mmol) MeSO 2NH 2, 24mg (5%mol) (DHQD) 2PHAL, and 8mgK 2OsO 2(OH) 4And 3～5ml trimethyl carbinol, 3～5ml H 2O (1: 1) after stirring, is chilled to 0 ℃, stirs 20 minutes, adds the isopropyl ether contain 245mg (0.5mmol) compound 1 (or ether, t-butyl methyl ether, butanone etc.) solution, stirs 16h in 0 ℃ to room temperature, and raw material disappears.0 ℃, add 0.75gNa 2SO 3Stirred 30 minutes under the room temperature.3 * 15ml ethyl acetate, 3 * 50ml 2NKOH, 3 * 50ml5%HCl, the saturated NaHCO of 3 * 50ml 3, the saturated NaCl washing of 3 * 50ml is neutral, anhydrous Na 2SO 4Dry remove desolvate spumescence solid crude product 274mg, rapid column chromatography gets compound 2223mg, yield 85%, d.e.99.74%
Compound 2:
[α] D 18+25.64°(C，1.04，CHCl 3)
MS(EI)(m/z)：506(M-H 2O)，400(M-HOCH 2OCH 3)，383(M+1-2HOCH 2CH 3-H 2O)，
IR(film)cm -1：3454(OH)，2944，1466，1378，1211，1037，
1HNMR (300MHz, CDCl 3) δ ppm:0.64 (3H, s, 18-H 3), 0.91 (3H, d, J=4.8Hz, 21-H 3) 0.93 (3H, s, 19-H 3),, 3.36 (3H, s, OCH 3), 3.37 (3H, s, OCH 3), 3.51 (1H, m, 3 β-H), 3.90 (1H, m, 6 β-H), 4.62 and 4.64 (2H, dd, J 1=J 2=6.80Hz, OCH 2O), 4.67 and 4.71 (2H, dd, J 1=J 2=6.80Hz, OCH 2O)
Embodiment 25 β-3,6-dimethoxy-methyl-3 α, 6 α, 24S, 25-tetrahydroxy courage steroid glycol 3
Figure C9912400700062
In the 25ml egg type bottle, add magneton, 245mg (0.5mmol) K 3Fe (CN) 6, 207mg (1.5mmol) K 2CO 3, 48mg (0.5mmol) MeSO 2NH 2, 27mg (5%mol) (DHQ) 2PHAL, and 6mgK 2OsO 2(OH) 4And 3～5ml trimethyl carbinol, 3～5mlH 2O (1: 1) after stirring, is chilled to 0 ℃, stirs 20 minutes, adds the glycol dimethyl ether contain 245mg (0.5mmol) compound 1 (or acetonitrile, t-butyl methyl ether, ether, 1,6-dioxane, N, N-dimethyl acetyl ammonia) solution.Stir 16h in 0 ℃ to room temperature, raw material disappears.0 ℃, add 0.75gNa 2SO 3Stirred 30 minutes under the room temperature.3 * 15ml ethyl acetate, 3 * 50ml 2NKOH, 3 * 50ml5%HCl, the saturated NaHCO of 3 * 50ml 3, the saturated NaCl washing of 3 * 50ml is neutral, anhydrous Na 2SO 4Drying, remove desolvate spumescence solid crude product 255mg, rapid column chromatography (pet: acetone/10: 1) compound 3229mg, yield 87% d.e.97.80%
Compound 3:
[α] D 18-22.89°(C，1.11，CHCl 3)
MS(EI)(m/z)：463(M-HOCH 2OCH 3)，399(M+1-HOCH 2OCH 3-2HOCH 3)，382(M-2HOCH 20CH 3-H 2O)，341((M-2HOCH 2OCH 3-H 2O)
IR(film)cm -1：3462(OH)，2943，2885，1467，1380，1146，1101，1037，
1HNMR(300MHz，CDCl 3)δppm：0.64(3H，s，18-H 3)，0.90(3H，s，19-H 3)，0.93(3H，d，J＝6.58Hz，21-H 3)，3.36(3H，s，OCH 3)，3.37(3H，s，OCH 3)，3.51(1H，m，3β-H)，3.90(1H，m，6β-H)，4.63(2H，s，OCH 2O)，4.67(2H，dd，J 1＝6.75Hz，J 2＝6.70Hz，OCH 2O)
Ultimate analysis (C 31H 56O 61/2H 2O): calculated value: C, 69.75%; H, 10.76%
Measured value: C, 69.64%; H, 10.92%
Embodiment 3 Δs 5-3-ethanoyl-3 β, 24R, 25-trihydroxy-courage steroid glycol 5
In the 25ml egg type bottle, add magneton, 1.158g (3.51mmol) K 3Fe (CN) 6, 484mg (3.51mmol) K 2CO 3, 105mg (1.13mmol) MeSO 2NH 2, 46mg (5%mol) (DHQD) 2PHAL, and 4mg (1%mol) K 2O sO 2(OH) 4And 15～20ml t-BuOH-H 2O (1: 1) after stirring, adds the N that contains 500mg (1.17mmol) raw material 4, dinethylformamide (or glycol dimethyl ether, acetonitrile, t-butyl methyl ether, 1,6-dioxane, N, N-dimethyl acetyl ammonia) solution, raw material disappears substantially behind the 20h, is chilled to 0 ℃, adds 1.755gNa 2SO 3Stir 2h.Add the 50ml ethyl acetate, 3 * 60ml 2NKOH, 3 * 60ml0%HCl, the saturated NaHCO of 3 * 60ml 3, the saturated NaCl washing of 3 * 60ml, anhydrous Na 2SO 4Dry remove desolvate crude product 623mg, behind the recrystallization compound 5441mg, yield 82%, 99.4%de.
Compound 5:
mp：162.4～163.8℃
[α]-25.28°(C，0.352，CHCl 3)
MS(EI)(m/z)：400(M-HOAc)，3?82(M-HOAc-H 2O)
IR(KBr)cm -1：3475(OH)，2965，2866，1733(CH 3CO 2)，1467，1376，1251，1035
1HNMR(300MHz，CDCl 3)δppm：0.69(3H，s，18-H 3)，0.94(3H，d，J＝6.26Hz，21-H 3)，1.02(3H，s，19-H 3)，1.16(3H，s，26-H 3)，1.22(3H，s，27-H 3)，2.04(3H，s，CH 3CO 2)，2.31(2H，d，J＝7.68Hz，7-H 2)，3.33(1H，m，24α-H)，4.60(1H，m，3α-H)，5.38(1H，d，J＝4.4Hz，6-H)
Ultimate analysis (C 29H 48O 4): calculated value: C, 75.61%; H, 10.50%
Measured value: C, 75.49%; H, 10.71%
Embodiment 4 Δs 5-3-ethanoyl-3 β, 24S, 25-trihydroxy-courage steroid glycol 6
In the 100ml egg type bottle, add magneton, 3.257g (9.87mmol) Tripotassium iron hexacyanide, 1.362g salt of wormwood (9.87mmol) 313mgCH 3SO 2NH 2, 128mg (5%mol) (DHQ) 2PHAL, 12mg (1%mol) K 2OsO 2(OH) 4And the mixing solutions of the 33ml trimethyl carbinol and water (1: 1), stirring and dissolving is to even yellow-green soln, add the glycol dimethyl ether contain 1.4g raw material 4 (or N, dinethylformamide, acetonitrile, 1,6-dioxane, N, N-dimethyl acetyl ammonia) solution, stirred 20 hours, and had a large amount of precipitations to separate out, be chilled to 0 ℃, adding the 4.93g S-WAT stirred 1 hour, 3 * 25ml ethyl acetate extraction is used 3 * 75ml 2N KOH respectively, 10% hydrochloric acid, saturated sodium bicarbonate and saturated common salt are washed to neutrality, anhydrous sodium sulfate drying, remove dissolve crude product 1.553g, behind the recrystallization compound 6:1.258 gram, productive rate 83.2%, 98.2%de.
Compound 6:
m.p.：134.9～135.8℃
[α] D 23-27.16°(C，0.928，CHCl 3)
MS(EI)(m/z)：400(M-HOAc)，382(M-HOAc-H 2O)
IR(film)cm -1：3445(OH)，1735(CH 3CO 2)，1469，1376，1248，1035
1HNMR(300MHz，CDCl 3)δppm：0.68(3H，s，18-H 3)，0.94(3H，d，J＝6.54Hz，21-H 3)，1.02(3H，s，19-H 3)，1.18(3H，s，25-H 3)，1.22(3H，s，26-H 3)，2.04(3H，s，CH 3CO 2)，2.32(2H，d，J＝8.23Hz，7-H 2)，3.28(1H，m，24β-H)，4.61(1H，m，3α-H)，5.38(1H，d，J＝4.73，6-H)
Ultimate analysis (C 29H 48O 41/4H 2O): calculated value: C, 74.88%; H, 10.5l%
Measured value: C, 75.08%; H, 10.70%
Embodiment 5 Δs 5-3-(dimethyl-tertiary butyl-silica-based)-3 β, 24R, 25-trihydroxy-courage steroid glycol 8
In the 25ml egg type bottle, add magneton, 495g K 3Fe (CN) 6, 207mg K 2CO 3, 48mg MeSO 2NH 2, 24mg (5%mol) (DHQD) 2PHAL and 4mg K 2O sO 2(OH) 4And 10ml t-BuOH-H 2O (1: 1) after stirring, adds 1 of 249mg raw material 7, the 6-dioxane (or N, dinethylformamide, glycol dimethyl ether, N, N-dimethyl acetyl ammonia) solution, reaction 20h is chilled to 0 ℃, adds Na 2SO 3Stir 2h.Add the 25ml ethyl acetate, 3 * 25ml2NKOH, 3 * 25ml0%HCl, the saturated NaHCO of 3 * 25ml 3, the saturated NaCl washing of 3 * 25ml, anhydrous Na 2SO 4Dry removing desolvated, and gets compound 8209mg, yield 78% behind the recrystallization.
Compound 8:
mp：186.0～187.2℃
[α] D 22-9.14°(C，0.504，CHCl 3)
MS-EI(m/z)：532(M +)，517(M-Me)，475(M-tBu)，458(M+1-H 2O-tBu)，440(M+1-tBu-2H 2O)
IR(KBr)cm -1：3420，2933，2860，1382，1254(Si-CH 3)，1096(Si-O)
1HNMR(300MHz，CDCl 3)δppm：0.05(6H，s，Si(CH 3) 2)，0.68(3H，s，18-H 3)，0.88(9H，s，SiC(CH 3) 3)，0.93(3H，d，J＝6.32Hz，21-H 3)，0.99(3H，s，19-H 3)，1.12(3H，s，26-H 3)，1.16(3H，s，27-H 3)，3.33(1H，t，J＝6.36Hz?24α-H)，3.47(1H，m，3α-H)，5.31(1H，d，J＝5.1Hz，6-H)，
Ultimate analysis: calculated value: C, 74.38%; H, 11.35%
Measured value: C, 74.03%; H, 11.51%
Embodiment 6 Δs 5-3-(dimethyl-tertiary butyl-silica-based)-3 β, 24S, 25-trihydroxy-courage steroid glycol 9
Figure C9912400700091
In the 50ml egg type bottle, add magneton, 1.812g (5.49mmol) K 3Fe (CN) 6, 758mg (5.49mmol) K 2CO 3, 174mg (1.83mmol) MeSO 2NH 2, 71mg (5%mol) (DHQ) 2PHAL and 20mg (1%mol) K 2O sO 2(OH) 4, and 12mlt-BuOH--H 2O (1: 1) after stirring, adds the N of 913mg (1.83mmol) raw material 7, N-dimethyl acetyl ammonia (or N, dinethylformamide, glycol dimethyl ether, t-butyl methyl ether, 1, the 6-dioxane) solution, raw material disappears substantially after 20 hours, is chilled to 0 ℃, adds 0.915gNa 2SO 3Stir 2H.Add the 50ml ethyl acetate, 3 * 100ml2NKOH, 3 * 100ml0%HCl, the saturated NaHCO of 3 * 100ml 3, the saturated NaCl washing of 3 * 100ml, anhydrous Na 2SO 4Dry remove desolvate crude product 0.919mg, recrystallization gets compound 9658mg, yield 67%.
Compound 9:
MS(EI)(m/z)：532(M +)，
IR(KBr)cm -1：3422，2935，2858，1382，1255(Si-CH 3)，1097(Si-O)，836
1HNMR(300MHz，CDCl 3)δppm：0.06(6H，s，Si(CH 3) 2)，0.68(3H，s，18-H 3)，0.88(9H，s，SiC(CH 3) 3)，0.91(3H，d，J＝5.06Hz，21-H 3)，1.00(3H，s，19-H 3)，1.17(3H，s，26-H 3)，1.22(3H，s，27-H 3)，3.28(1H，d，J＝8.87Hz，24β-H)，3.48(1H，m，3α-H)，5.30(1H，d，J＝3.36Hz，6-H)，
Ultimate analysis: calculated value: C, 74.38%; H, 11.35%
Measured value: C, 74.21%; H, 11.36%
Embodiment 75 β-3 β, 7 α, 24S, 25-tetrahydroxy courage steroid tetrol 11
Figure C9912400700101
In the 25ml egg type bottle, add magneton, 496mg (1.5mmol) Tripotassium iron hexacyanide, 208mg salt of wormwood (1.5mmol), 48mgCH 3SO 2NH 2, 24mg (5%mol) (DHQ) 2PHAL, 8mg (1%mol) K 2OsO 2(OH) 4And the mixing solutions of 3～5ml trimethyl carbinol and water (1: 1), stirring and dissolving is to even yellow-green soln, add the acetonitrile contain 201mg raw material 10 (or N, dinethylformamide, glycol dimethyl ether, 1,6-dioxane, N, N-dimethyl acetyl ammonia) solution, stirred 20 hours, and had a large amount of precipitations to separate out, be chilled to 0 ℃, adding the 0.75g S-WAT stirred 0.5 hour, 3 * 15ml ethyl acetate extraction is used 3 * 50ml 2N KOH respectively, 10% hydrochloric acid, saturated sodium bicarbonate and saturated common salt are washed to neutrality, anhydrous sodium sulfate drying, remove dissolve crude product 200mg, behind the recrystallization compound 11:185mg, productive rate 85%, 99.3%de.
Compound 11:
MS(EI)(m/z)：400(M-2H 2O)，385(M-2H 2O-Me)
IR(film)cm -1：3445(OH)，1469，1376，1248，1035
1HNMR(300MHz，CDCl 3)δppm：0.66(3H，s，18-H 3)，0.82(3H，s，19-H 3)，0.91(3H，d，J＝6.67Hz，21-H 3)，1.19(3H，s，26-H 3)，1.23(3H，s，27-H 3)，3.29(1H，m，24β-H)，3.53(1H，m，3α-H)，3.85(1H，m，7β-H)，
Embodiment 85 β-3 β, 7 α, 24R, 25-tetrahydroxy courage steroid tetrol 12
In the 25ml egg type bottle, add magneton, 496mg (1.5mmol) Tripotassium iron hexacyanide, 208g salt of wormwood (1.5mmol), 48mg CH 3SO 2NH 2, 24mg (5%mol) (DHQD) 2PHAL, 8mg (1%mol) K 2OsO 2(OH) 4And the mixing solutions of 3～5ml trimethyl carbinol and water (1: 1), stirring and dissolving is to even yellow-green soln, add the glycol dimethyl ether contain 201mg raw material 10 (or N, dinethylformamide, acetonitrile, acetone, 1, the 6-dioxane, N, N-dimethyl acetyl ammonia) solution, stirred 20 hours, there are a large amount of precipitations to separate out, be chilled to 0 ℃, add the 0.75g S-WAT and stirred 3 * 15ml ethyl acetate extraction 0.5 hour, use 3 * 50ml 2N KOH respectively, 10% hydrochloric acid, saturated sodium bicarbonate and saturated common salt are washed to neutrality, anhydrous sodium sulfate drying, remove dissolve crude product 200mg, get compound 12:187mg, productive rate 86%, 100%de behind the recrystallization.
Compound 12:
MS(EI)(m/z)：400(M-2H 2O)，385(M-2H 2O-Me)
IR(film)cm -1：3448(OH)，1463，1385，1245，1008
1HNMR(300MHz，CDCl 3)δppm：0.64(3H，s，18-H 3)，0.80(3H，s，19-H 3)，0.92(3H，d，J＝6.67Hz，21-H 3)，1.17(3H，s，26-H 3)，1.20(3H，s，27-H 3)，3.32(1H，m，24α-H)，3.52(1H，m，3α-H)，3.82(1H，m，7β-H)，
Embodiment 93-dioxolane-7 alpha-methoxymethyl alkane-7 α, 24S, 25-trihydroxy-courage steroid glycol 14
Figure C9912400700111
In the 25ml egg type bottle, add magneton, 496mg (1.5mmol) Tripotassium iron hexacyanide, 208mg salt of wormwood (1.5mmol), 48mg CH 3SO 2NH 2, 24mg (5%mol) (DHQ) 2PHAL, 8mg (1%mol) K 2OsO 2(OH) 4And the mixing solutions of 3～5ml trimethyl carbinol and water (1: 1), stirring and dissolving is to even yellow-green soln, add the tetrahydrofuran (THF) contain 244g raw material 13 (or N, dinethylformamide, second cyanogen, 1,6-dioxane, N, N-dimethyl acetyl ammonia) solution, stirred 20 hours, and had a large amount of precipitations to separate out, be chilled to 0 ℃, adding the 0.75g S-WAT stirred 0.5 hour, 3 * 15ml ethyl acetate extraction is used 3 * 50ml 2N KOH respectively, 10% hydrochloric acid, saturated sodium bicarbonate and saturated common salt are washed to neutrality, anhydrous sodium sulfate drying, remove dissolve crude product 245mg, behind the recrystallization compound 14:219mg, productive rate 84%, 99%de.
Compound 14:
MS(EI)(m/z)：460(M-HOCH 2OCH 3)，442(M-HOCH 2OCH 3-H 2O)，427(M-HOCH 2OCH 3-H 2O-Me)
IR(film)cm -1：3445(OH)，1470，1377，1249，1038
1HNMR(300MHz，CDCl 3)δppm：0.64(3H，s，18-H 3)，0.81(3H，s，19-H 3)，0.92(3H，d，J＝6.68Hz，21-H 3)，1.17(3H，s，25-H 3)，1.21(3H，s，26-H 3)，3.28(1H，m，24β-H)，3.36(3H，s，OCH 3)3.64(1H，m，7β-H)，3.91(4H，m，sharp，OCH 2CH 2O)，4.64(2H，m，OCH 2O)
Embodiment 103-dioxolane-7 alpha-methoxymethyl alkane-7 α, 24R, 25-trihydroxy-courage steroid glycol 15
Figure C9912400700121
In the 25ml egg type bottle, add magneton, 496mg (1.5mmol) Tripotassium iron hexacyanide, 208mg salt of wormwood (1.5mmol), 48mg CH 3SO 2NH 2, 24mg (5%mol) (DHQD) 2PHAL, 8mg (1%mol) K 2OsO 2(OH) 4And the mixing solutions of 3～5ml trimethyl carbinol and water (1: 1), stirring and dissolving is to even yellow-green soln, add the glycol dimethyl ether contain 244g raw material 13 (or N, dinethylformamide, acetonitrile, 1,6-dioxane, N, N-dimethyl acetyl ammonia) solution, stirred 20 hours, and had a large amount of precipitations to separate out, be chilled to 0 ℃, adding the 0.75g S-WAT stirred 0.5 hour, 3 * 15ml ethyl acetate extraction is used 3 * 50ml 2N KOH respectively, 10% hydrochloric acid, saturated sodium bicarbonate and saturated common salt are washed to neutrality, anhydrous sodium sulfate drying, remove dissolve crude product 250mg, behind the recrystallization compound 15:227mg, productive rate 87%, 99.6%de.
Compound 15:
MS(EI)(m/z)：460(M-HOCH 2OCH 3)，442(M-HOCH 2OCH 3-H 2O)
IR(film)cm -1：3448(OH)，1468，1375，1245，1031
1HNMR(300MHz，CDCl 3)δppm：0.65(3H，s，18-H 3)，0.81(3H，s，19-H 3)，0.92(3H，d，J＝6.65Hz，21-H 3)，1.18(3H，s，25-H 3)，1.22(3H，s，26-H 3)，3.29(1H，m，24α-H)，3.37(3H，s，OCH 3)3.62(1H，m，7β-H)，3.92(4H，m，sharp，OCH 2CH 2O)，4.65(2H，m，OCH 2O)

Claims (14)

1. 24R, 25-or 24S, the synthetic method of 25-dihydroxyl steroidal compounds, above-mentioned 24R, 25-or 24S, the structural formula of 25-dihydroxyl steroidal compounds is as follows:
Figure C9912400700021
There is down Δ in the mixed solvent catalyst neutralisation that this method is included in tertiary butanol and water 24-steroidal compounds and K 3Fe (CN) 6, K 2CO 3, CH 3SO 2NH 2React to room temperature at 0 ℃, selected catalyzer is K 2OsO 2(OH) 4(DHQD) 2PHAL or (DHQ) 2PHAL is characterized in that adding second kind of solvent, reacts 10～20 hours, and described second kind of solvent is glycol dimethyl ether, t-butyl methyl ether, ether, isopropyl ether, acetone or butanone, described Δ 24-steroidal compounds has following structural formula:
R wherein 1Or R 2Be the methoxy methyl ether, THP trtrahydropyranyl, acetoxyl group, OCH 2CH 2O, OH, H, benzoyl, methanesulfonates, p-toluenesulfonic esters, tertiary butyl dimethyl-silicon ether or benzyl; Or R 1R 2Be O; R 3Be α-or β-H, or R 3R 4Be two keys, R 4Or R 5Be the methoxy methyl ether, THP trtrahydropyranyl, acetoxyl group, OCH 2CH 2O, OH, H, PhCOO, MeSO 2O or p-toluenesulfonic esters; Or R 4R 5Be O, R 6Or R 7Be the methoxy methyl ether, THP trtrahydropyranyl, acetoxyl group, OCH 2CH 2O, OH, H, benzoyl, MeSO 2O or p-toluenesulfonic esters; Or R 6R 7Be O.
2. a synthetic method as claimed in claim 1 is characterized in that described Δ 24-steroidal compounds, K 3Fe (CN) 6, K 2CO 3, CH 3SO 2NH 2, K 2OsO 2(OH) 4, 1, two (9-O the dihydro-quinidine)-2 or 1 of 4-, two (the 9-O dihydro Kui Buddhist nuns)-2 of 4-, 3-diaza Cai's mol ratio is 1: 1～5: 1: 1～5: 0.5～3: 0.005～0.01.
3. a synthetic method as claimed in claim 1 is characterized in that in the mixed solvent of described tertiary butanol and water, and the volume ratio of the trimethyl carbinol and water is 1: 0.5～2.
4. one kind as claim 1 and 3 described synthetic methods, and the consumption that it is characterized in that described tertiary butanol and water mixed solvent is every mole of Δ 24Steroidal compounds adds the mixing solutions of 1～10 liter tertiary butanol and water.
5. a synthetic method as claimed in claim 1 is characterized in that by Δ 24-5 β-3 α, 6 alpha, alpha-dimethyl oxygen ylmethyl-courage steroids are synthetic 5 β-3 α of raw material, 6 alpha, alpha-dimethyl oxygen ylmethyl-3 α, 6 α, 24R, 25-tetrahydroxy courage steroid.
6. a synthetic method as claimed in claim 1 is characterized in that by Δ 24-5 β-3 α, 6 alpha, alpha-dimethyl oxygen ylmethyl-courage steroids are synthetic 5 β-3 α of raw material, 6 alpha, alpha-dimethyl oxygen ylmethyl-3 α, 6 α, 24S, 25-tetrahydroxy courage steroid.
7. a synthetic method as claimed in claim 1 is characterized in that by Δ 5,24-3 β-acetoxyl group-courage steroid is the synthetic Δ of raw material 5-3 β-acetoxy-3 β, 24R, 25-trihydroxy--courage steroid.
8. a synthetic method as claimed in claim 1 is characterized in that Δ 5,24-3 β-acetoxyl group-courage steroid is the synthetic Δ of raw material 5-3 β-acetoxy-3 β, 24S, 25-trihydroxy--courage steroid.
9. a synthetic method as claimed in claim 1 is characterized in that Δ 5,24-3 β-(tertiary butyl-dimethyl) be silica-based-and the courage steroid is the synthetic Δ of raw material 5Silica-based-3 β of-3 β-(tertiary butyl-dimethyl), 24R, 25-trihydroxy--courage steroid.
10. a synthetic method as claimed in claim 1 is characterized in that Δ 5,24-3 β-(tertiary butyl-dimethyl) be silica-based-and the courage steroid is the synthetic Δ of raw material 5Silica-based-3 β of-3 β-(tertiary butyl-dimethyl), 24S, 25-trihydroxy--courage steroid.
11. a synthetic method as claimed in claim 1 is characterized in that Δ 24-5 β-3 β, 7 alpha-dihydroxy-courage steroids are synthetic 5 β-3 β of raw material, 7 α, 24S, 25-tetrahydroxy courage steroid.
12. a synthetic method as claimed in claim 1 is characterized in that Δ 24-5 β-3 β, 7 α ,-dihydroxyl courage steroid are synthetic 5 β-3 β of raw material, 7 α, 24R, 25-tetrahydroxy courage steroid.
13. a synthetic method as claimed in claim 1 is characterized in that Δ 24-3-dioxolane-7 alpha-methoxymethyl alkane-courage steroid is synthetic 3-dioxolane-7 alpha-methoxymethyl alkane-7 α of raw material, 24S, 25-trihydroxy-courage steroid.
14. a synthetic method as claimed in claim 1 is characterized in that Δ 24-3-dioxolane-7 alpha-methoxymethyl alkane-courage steroid is to be synthetic 3-dioxolane-7 alpha-methoxymethyl alkane-7 α of raw material, 24R, 25-trihydroxy-courage steroid.
CN99124007A 1999-11-12 1999-11-12 High-stereoselectivity synthesization of 24R,25- and 24S, 25-dihydroxysteroid Expired - Fee Related CN1098273C (en)

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