CN1299821A - Lactone compound and its synthesis and use - Google Patents

Lactone compound and its synthesis and use Download PDF

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CN1299821A
CN1299821A CN 00127974 CN00127974A CN1299821A CN 1299821 A CN1299821 A CN 1299821A CN 00127974 CN00127974 CN 00127974 CN 00127974 A CN00127974 A CN 00127974A CN 1299821 A CN1299821 A CN 1299821A
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steroid
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ring
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lactone
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CN1120844C (en
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田伟生
李民
殷海峰
汤小虎
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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 lactone compound, synthesis method and application. It polar solvent a peroxyorganic acid is used to oxidate steroid sapogenin to obtain steroid lactone with C22 and 3 methyl-gamma-butyrolactone. Said steroid lactone is undergone the process of hydrolysis, Jone's reagent oxidation, Huang Min-long reduction, ether reaction, rearrangement, dehalogenation reaction or photochemical reaction and oxidation reaction to obtain other lactone. It can be used for synthesizing chiral methyl contained compounds of chiral liquid crystal and insect pheromone, etc. and natural steroid molecules of pyrazine double steroid and brassnosteroid, and synthesizing steroid medicine. Said invention is moderate in reaction condition, low in cost and high in yield, and has no pollution.

Description

Lactone compound, preparation method and use
The present invention relates to the novel lactone compound of a class, degraded obtains the method for this compound and the purposes of degraded product.
Steroid sapogenines, as diosgenin, sisalagenin, zhimusaponin unit, luxuriant numb saponin and analogue thereof are to make various steroid drugs important chemical material always, and China has abundant steroid sapogenines resource, and diosgenin is the basis of China's steroidal industry.Steroid sapogenines resource how to utilize China rationally and effectively is reality and urgent problem.Yet utilize steroid sapogenines synthesizing steroid medicine, at first need steroid sapogenin degradation is become pregnant steroid or androstane.Up to now, the sophisticated degradation method of having reported mainly contains two kinds: 1.1947 years by the disclosed (J.Am.Chem.Soc.1947 of Marker R.E., 69,2167) in autoclave, steroid sapogenines and diacetyl oxide are heated to 200 ℃ are cracked into false steroid sapogenines, again through the chromic anhydride oxidation and the method that obtains corresponding Progesterone after eliminating reaction.Three step total yields are approximately 60%.With the sisalagenin is example, and reaction formula is as follows: Although after this constantly there is the chemist that this method is improved, only limit to the conversion (Micovic I.V.Synthesis, 1990,591) to reaction reagent, and fail to change many defectives of this method: the acetic anhydride consumption is big in the reaction; The suffered corrosion of conversion unit is strong; Reaction conditions is abominable; Waste liquid and waste residue that reaction produces bring environmental pollution.These problems are also perplexing people always.2.1996 year disclosed (Chinese patent, application number: 96116304.6) by the oxidation of organic peroxide acid to steroid sapogenines, basic hydrolysis obtains having the method for the pregnen alcohol of three chiral carbon, and two step total yields can reach more than 90% by Tian Weisheng professor.With the sisalagenin is example, and reaction formula is as follows: It is the peer-to-peer of Progesterone that the pregnen alcohol that this method obtains can be considered.
One of purpose of the present invention provides the novel lactone compound of a class.
Two of purpose of the present invention provides the method that a kind of degradation of steroid sapogenin becomes lactone.
Three of purpose of the present invention provides the purposes of above-claimed cpd.Compound of the present invention has following general molecular formula: In the formula, during M=H, Y=
Figure 0012797400054
During the M=Alpha-Methyl, Y has following molecular formula:
Figure 0012797400061
Among the Y, n or m=0 or 1, the p=singly-bound or-O-, R 1=H is perhaps with R 2Or R 10Be connected to two keys of A ring; R 2=H is perhaps with R 1Or R 3Be connected to two keys of A ring;
R 3=H, OH ,=O, CH 3O, CH 3COO, CH 3OCH 2O, C 6H 5COO, C 6H 5CH 2O, R fSO 3, perhaps with R 2Be connected to two keys of A ring, wherein R f=HCF 2CF 2OCF 2CF 2, CF 3(CF 2) 7, CF 3(CF 2) 3, CF 3Or CH 3OOCCF 2
R 4=H is perhaps with R 5Be connected to two keys of A ring;
R 5=H, X, OH are perhaps with R 4Or R 6Be connected to two keys of A ring or B ring, perhaps with R 6Be connected to-O-;
R 6=H, OH, X, CH 3COO is perhaps with R 1Be connected to-CH 2-O-is perhaps with R 5Be connected to two keys of B ring, perhaps with R 5Be connected to-O-, perhaps with R 10Be connected to-CH 2-O-, wherein K=F, Cl, Br or I;
R 10=H, CH 3, CH 2OH is perhaps with R 6Be connected to-CH 2-O-;
R 12=H ,=O, CH 3COO or CH 3OCH 2O;
R 13=H、CH 3、OH、CH 3COO；
R 14And R 15=H or be connected to two keys on the D ring;
R 16Or R 17=H or OH;
The valence mumber of carbon is 4 in the above-mentioned molecular formula, and works as R 1, R 2, R 4, R 5, R 6, R 9, R 11, R 12, R 14, R 15, R 16And R 17All=H, and R 10And R 13=CH 3The time, R 3≠ CH 3COO.
Figure 0012797400062
Figure 0012797400063
R in the formula 1, R 2, R 3, R 4, R 5, R 6, R 10, R 12, R 13, R 14, R 15, R 16And R 17Definition and the restriction as previously mentioned.
In a word, compound of the present invention can be
Figure 0012797400064
Or
Figure 0012797400065
For example: 5 α-3 β-acetoxyl group-22-steroid acid-16-alcoholic lactone, 5 α-3 beta-hydroxies-22-steroid acid-16-alcoholic lactone, 5 α-3-oxo-22-steroid acid-16-alcoholic lactone, 5 α-22-steroid acid-16-alcoholic lactone, 5 α-3 β, 12 β-acetoxyl group-22-steroid acid-16-alcoholic lactone, 5 β-3 β-acetoxyl group-22-steroid acid-16-alcoholic lactone, 5 α-3 β-mesyloxy-6 α-acetoxyl group-22-steroid acid-16-alcoholic lactone, 3 beta-acetoxyl group-5 α, 6 alpha-oxo-s-22-steroid acid-16-alcoholic lactone, 3 β, 6 beta-acetoxyl group-5 alpha-hydroxy-2 2-steroid acid-16-alcohol ester that contracts, 3 β-acetoxyl group-12-ketone-22-steroid acid-16-alcoholic lactone, 3 β-acetoxyl group-12-ketone-C-height-13-oxa--22-steroid acid-16-alcoholic lactone, 3 beta-hydroxies-5-bromo-6 (19)-epoxies-22-steroid acid-16-alcoholic lactone, 3-oxo-19-methylol-Gao-steroid-4 alkene-22-acid-16-alcoholic lactone, 3-oxo-10 (19)-methylene base-steroid-1-alkene-22-acid-16-alcoholic lactone, 3-(5H-3-oxo octafluoro pentyl sulfonyloxy)-10 (19)-methylene bases-5 (10)-disconnected-steroid-1 (10), 2,4-triolefin-22-acid-16-alcoholic lactone, 3 β, 12 β-bi-methoxy methyl-hydroxy-16 alpha--hydroxyl-22-steroid acid-16-alcoholic lactone, 3 β, 12 β-bi-methoxy methyl-22-steroid acid-16-alcoholic lactone, 3 β, 12 β-bi-methoxy methyl-17 Alpha-hydroxy-22-steroid acid-16-alcoholic lactone, 3 β-benzyloxy-5 α, 6 beta-2-dibroms-22-steroid acid-16-alcoholic lactone, 3 β-benzyloxy-5-alkene-22-steroid acid-16-alcoholic lactone, 3 β-acetoxyl group-12-oxo-5-steroid-14 (15)-alkene-22-acid-16-alcoholic lactone, 3 (R)-methyl-gamma-butyrolactones etc.
The inventive method is in polar solvent, by of the oxidation of peroxide organic acid to steroid sapogenines, add the excessive oxygenant of reductive agent reduction after the reaction, obtain lactone compound through after the conventional aftertreatment again, perhaps aforementioned lactone compound is further reacted synthetic other lactone compound, product has following general molecular formula:
Figure 0012797400071
In the formula, during M=H, Y= During the M=Alpha-Methyl, Y has following molecular formula:
Figure 0012797400073
Among the Y, n or m=0 or 1, the p=singly-bound or-O-,
R 1=H is perhaps with R 2Or R 10Be connected to two keys of A ring;
R 2=H is perhaps with R 1Or R 3Be connected to two keys of A ring;
R 3=H, OH ,=O, CH 3O, CH 3COO, CH 3OCH 2O, C 6H 5COO, C 6H 5CH 2O, R fSO 3, perhaps with R 2Be connected to two keys of A ring, wherein R f=HCF 2CF 2OCF 2CF 2, CF 3(CF 2) 7, CF 3(CF 2) 3, CF 3Or CH 3OOCCF 2
R 4=H is perhaps with R 5Be connected to two keys of A ring;
R 5=H, X, OH are perhaps with R 4Or R 6Be connected to two keys of A ring or B ring, perhaps with R 6Be connected to-O-;
R 6=H, OH, X, CH 3COO is perhaps with R 1Be connected to-CH 2-O-is perhaps with R 5Be connected to two keys of B ring, perhaps with R 5Be connected to-O-, perhaps with R 10Be connected to-CH 2-O-, wherein X=F, Cl, Br or I;
R 10=H, CH 3, CH 2OH is perhaps with R 6Be connected to-CH 2-O-;
R 12=H ,=O, CH 3COO or CH 3OCH 2O;
R 13=H、CH 3、OH、CH 3COO；
R 14And R 15=H or be connected to two keys on the D ring;
R 16Or R 17=H or OH;
The valence mumber of carbon is 4 in the above-mentioned molecular formula;
This method specifically comprises the steps:
In polar solvent and 0-60 ℃ the time, the mol ratio of organic oxidizing agent, steroid sapogenines and reaction additives is 1.0-2.5: 1: 0.0005-1 is recommended as 1.5-2: 1: 0.001-0.2, reacted 5-40 hour.Described reaction additives is bromine, iodine or its salt.The organic oxidizing agent of the available reductive agent decomposing excessive in reaction back.Organism washs through extraction, drying, and after concentrated a series of conventional aftertreatments, with alcohol or alcohol-ether, alcohol-ester solvent obtains the steroidal lactone compound of colourless crystallization to the crude product recrystallization.Mother liquor behind stripped water and the recrystallization is by extracting once more with ether solvent, and drying concentrates, and aftertreatments such as underpressure distillation get 3 (R)-methyl-gamma-butyrolactones in addition.
97106575.6) etc. above-mentioned steroidal lactone compound can be by with conventional hydrolysis, Jone ' s reagent oxidation, Huang Min-lon reduction, ether reaction, the dehalogenation reaction, photochemical/oxidizing reaction and rearrangement reaction (Chinese patent, application number: the arbitrary step in or a few stepping and obtain other steroidal lactone compound.Wherein said rearrangement reaction is that the mol ratio of substrate, sulfonated reagent RfSO2F and alkali is 1 in the time of organic solvent neutralization-5-30 ℃: 1-10: 2-20, reacted 5-24 hour, Rf as previously mentioned, alkali comprises pyridine, 2,6-lutidine, N (CH 3) 3, [(CH 3) 2CH] 2NH, Na 2CO 3, NaH, (CH 3) 3COK, NaOH, KOH, NH 3, 1,5-diazabicyclo [4.3.0] nonane-5-alkene (DBN), 1,8-diazabicyclo [5.4.0] undecane-7-alkene (DBU) and (C 4H 9) 4NF etc.Remaining reaction is all operated routinely and is carried out.
Reaction formula is as follows:
Figure 0012797400081
Described organic oxidizing agent comprises: peroxy trifluoroacetic acid, Peracetic Acid, benzoyl hydroperoxide, a halogen benzoyl hydroperoxide, adjacent formic acid benzoyl hydroperoxide, single peroxy maleic acid, the magnesium salts of monoperphthalic acid, the benzoyl hydroperoxide that nitro replaces, dibenzoyl peroxide, peroxy tert-butyl alcohol, the organic oxidation reagent of peroxide sulfonic acid etc. and other fat and fragrance;
Described steroid sapogenines comprises: described steroid sapogenines comprises natural sapogenin and the analogue that is formed by natural sapogenin modification, as diosgenin (Diosgenin), sisalagenin (Tigogenin), zhimusaponin unit (Sarsarsapogenin), the noisy sapogenin (pennogenin) of spray, rockogenin (Rocogenin), luxuriant numb sapogenin (Hecogenin), 5 α-3 β-mesyloxy-6 α-acetoxyl group-steroid sapogenines, 3 β, 6 beta-acetoxyl group-5 Alpha-hydroxy-steroid sapogeniness, 3 beta-hydroxies-5-bromo-6 (19)-epoxies-steroid sapogenines, the rockogenin diacetate esters, zhimusaponin unit acetic ester, the diosgenin acetic ester, luxuriant numb sapogenin acetic ester etc.;
Described bromine, iodine or its salt comprise: the organic salt of bromine, iodine, bromine or iodine or the inorganic salt of bromine or iodine, and as Sodium Bromide, lithiumbromide, magnesium bromide, sodium iodide, potassiumiodide, tetrabutylammonium iodide etc.;
Described polar solvent comprises: methylene halide, haloform, tetrahydrofuran (THF), ether, isopropyl ether, methyl alcohol, ethanol, the trimethyl carbinol, methyl-sulphoxide, N, halohydrocarbon such as dinethylformamide, ethers, alcohols, proton or aprotic polar solvents such as amides;
Described reductive agent comprises: S-WAT, sodium bisulfite, pyrosulphite hydrogen sodium, Sulfothiorine, vat powder etc.;
Described alcohol comprises: methyl alcohol, ethanol, Virahol, the trimethyl carbinol, propyl carbinol etc.;
Described ether comprises: ether, isopropyl ether, glycol dimethyl ether etc.;
Described ester comprises: ethyl acetate, ethyl formate, isopropyl acetate, t-butyl formate etc.
Present method gained steroidal lactone can be considered 22-steroid aldehyde, the acid of 22-steroid, 16-sterol, 16-steroid alkene, the precursor of a series of steroidal compounds such as 15-steroid alkene.Many steroidal molecules that significant physiologically active is arranged of Fa Xianing up to now much all have on 22 bit functions group or the D ring and contain functional group, have or even these two position height functionalization.The Cephalostatine (Tian Weisheng etc., Acta Pharmaceutica Sinica, 1999,34,552) and the OSW-1 (Mimaki, Y.etat Phytochemistry, 1992,31,3969) that for example have strong anti-tumor activity; Has the Brassicasterin (Tian Weisheng, organic chemistry, 1984,4,259) that promotes the plant-growth effect; Have active steroid sapogenines of multiple important biomolecule and saponin thereof, as (Zhang Jianbo etc., organic chemistry, 2000,20,663) such as Pennogenin.The resultant novel steroidal lactone compound of the present invention can make the synthetic approach more succinct, effectively as the intermediate that synthesizes these bioactive steroids molecules.This class lactone is transformed a little, just can obtain the structure of 16 chiral hydroxyl groups and 22 aldehyde.Because the existence of 22 and 16 these two functional groups makes the C14-C22 position of steroidal molecule all obtain activation, thereby lays the foundation for the synthetic of bioactive molecules.Moreover, this class steroidal lactone can also further obtain pregnant steroid or androstane by known chemical conversion, thereby is used for the synthetic of steroid drugs.
Another lactone 3 (R)-methyl-gamma-butyrolactone of present method gained then can become synthesis of chiral methyl side compound, as chiral liquid crystal, and insect pheromone, the important source material of vitamin-E etc.
Compared with prior art, the invention provides the new lactone compound of a class; The inventive method can easy and effective degradation of steroid sapogenin, and its reaction conditions gentleness can at room temperature be carried out; Operation is easy, need not special equipment; Step is brief; Reaction yield height can reach 80-95%; Because of the acetate that is produced in the reaction, boiling points such as trifluoroacetic acid are low, can recycle and not have environmental pollution, and what consume in the real reaction is hydrogen peroxide, so reaction cost is low; Product steroidal lactone not only can be used for synthetic many active steroidal molecules, also can be used for the synthetic of steroid drugs; Product 3 (R)-methyl-gamma-butyrolactone then can become the important source material of synthesis of chiral methyl chains compound.
Following examples help to understand the present invention, but are not limited to the present invention.
Embodiment 1:
5 α-3 β-acetoxyl group-22-steroid acid-16-alcoholic lactone:
The trifluoroacetic anhydride of the peroxy trifluoroacetic acid of new system: 0.5ml is dissolved in the anhydrous CH of 2ml 2Cl 2In, be chilled to 0 ℃, add 96% the H of 0.5ml slowly 2O 2Solution dropwises in the 10mins, and insulation is warming up to the peroxy trifluoroacetic acid solution that stirring at room 30mins just obtains new system behind 0 ℃ of vigorous stirring 30mins.
Steroid sapogenines 10mmol is dissolved in 50mlCH 2Cl 2In, stirring adds 260mg (1mmol) I2 down, is chilled to 0 ℃, drips the trifluoro peracetic acid soln of new system lentamente, finishes in the 30mins, continues insulation and after 1 hour, is warming up to room temperature 0 ℃ of stirring, and TLC tracks to raw material and disappears; In reaction flask, add the saturated Na of 5ml 2S 2O 3Solution, vigorous stirring is to solution look, 3 * 10mlCH 2Cl 2Extract, merge organic phase, use saturated NaHCO successively 3Wash, washing, saturated common salt is washed to neutrality, anhydrous MgSO 4Dried overnight concentrates, the contract crude product of ester cpds of 22-steroid acid-16-alcohol.Crude product is selected the appropriate solvent recrystallization for use, gets the pure product of steroidal lactone. Press aforesaid operations, obtain 5 α-3 β-acetoxyl group-22-steroid acid-16-alcoholic lactone from sisalagenin (Tigogenin).Yield: 82%.[α]=-46.34°(c,3.7,CHCl 3)mp：222-224℃ 1HNMR(300MHz,CDCl3)δ：4.9-5.0(m,1H,16-H),4.6-4.7(m,1H,3-H),2.2-2.3(m,1H,20-H)2.5-2.6(dd,J=6.9Hz,J=0.7Hz,1H,17-H),2.1(s,3H,CH3CO-),1.2(d,J=11.4Hz,3H,21-H),0.9(s,3H,18-H),0.8(s,3H,19-H)ppm.EIMS(m/z,％)328(M +-60),288(20.96),273(76.42),215(88.16),165(73.34),107(100),93(93.19),79(80.56)。Ultimate analysis: (C 24H 36O 4) theoretical value: C%74.23, H%9.28
Measured value: C%74.37, H%9.29.
5 α-3 beta-hydroxies-22-steroid acid-16-alcoholic lactone 5 α-3 β-acetoxyl group-22-steroid acid-16-alcoholic lactone gets 5 α-3 beta-hydroxies-22-steroid acid-16-alcoholic lactone accordingly with the ordinary method hydrolysis.Hydrolysis reaction adds alkali such as NaOH, KOH or LiOH in aqueous ethanol isopolarity solvent and 0-60 ℃ the time, mole dosage be substrate 1-20 doubly, reacted 0.5-10 hour.HNMR(300MHz,CDCl 3)δ：4.8-5.0(m,1H,16-H),3.6-3.7(m,1H,3-H),2.2-2.3(m,1H,20-H)2.5-2.6(dd,J=6.9Hz,J=0.7Hz,1H,17-H),1.2(d,J=11.4Hz,3H,21-H),0.9(s,3H,18-H),0.8(s,3H,19-H)ppm.EIMS(m/z,％)328(M-H 2O),288(20.96),273(76.42),215(88.16),165(73.34),107(100),93(93.19),79(80.56)。
5 α-3-oxo-22-steroid acid-16-alcoholic lactone 5 α-3 beta-hydroxies-22-steroid acid-16-alcoholic lactone obtains corresponding 5 α-3-oxo-22-steroid acid-16-alcoholic lactone through Jone ' s reagent oxidation.Reaction is in the acetone equal solvent and during room temperature-60 ℃, CrO 3/ H 2SO 4Or H 2CrO 4/ H 2SO 4With the mol ratio of substrate be 1-5: 1, reacted 0.5-10 hour.HNMR(300MHz,CDCl 3)δ：4.9-5.0(m,1H,16-H),2.2-2.3(m,1H,20-H)2.5-2.6(dd,J=6.9Hz,J=0.7Hz,1H,17-H),1.2(d,J=11.4Hz,3H,21-H),0.9(s,3H,18-H),0.8(s,3H,19-H)ppm.EIMS(m/z,％)344(M +)。
5 α-22-steroid acid-16-alcoholic lactone 5 α-3-oxo-22-steroid acid-16-alcoholic lactone obtains corresponding 5 α-22-steroid acid-16-alcoholic lactone through Huang Min-lon reduction (J.O.C, 1983,48,1404).Reaction is in the ethanol equal solvent, and the mol ratio of substrate and hydrazine hydrate is 1: 1-5, back flow reaction 0.5-10 hour.HNMR(300MHz,CDCl 3)δ：4.9-5.0(m,1H,16-H),2.1-2.3(m,1H,20-H)2.4-2.6(dd,J=6.9Hz,J=0.7Hz,1H,17-H),1.24(d,J=11.4Hz,3H,21-H),0.9(s,3H,18-H),0.8(s,3H,19-H)ppm.EIMS(m/z,％)328(M +)。
Embodiment 2:5 α-3 β, 12 β-acetoxyl group-22-steroid acid-16-alcoholic lactone:
Figure 0012797400111
Steroid sapogenines rockogenin (Rocogenin) diacetate esters 10mmol is dissolved in the 50ml ether, stirs to add 0.5mmolKI down, and 40 ℃, drip the peracetic acid soln of new system lentamente, stir, TLC tracks to raw material and disappears; In reaction flask, add the saturated Na of 5ml 2SO 3Solution, vigorous stirring is to solution look, 3 * 10mlCHCl 3Extract, merge organic phase, use saturated NaHCO successively 3Wash, washing, saturated common salt is washed to neutrality, anhydrous MgSO 4Dried overnight concentrates, and recrystallization obtains 5 α-3 β, 12 β-acetoxyl group-22-steroid acid-16-alcoholic lactone.Yield: 87%.[α]=-15.49 ° (c, 0.24, CHCl 3) mp:118-119 ℃ IR (KBr) 2937,2854,1774,1735,1456,1374,1247,963cm -1HNMR (300MHz, CDCl 3) δ: 5.0 (m, 1H, 16-H), 4.6-4.7 (dd, J=11.4Hz, J=4.7Hz, 1H, 12-H), 4.6 (m, 1H, 3-H), 2.5 (m, 1H, 17-H), 2.2 (m, 1H, 20-H), 2.1 (s, 3H, CH 3CO-), 2.0 (s, 3H, CH 3CO-), 1.2 (d, J=4.0Hz, 3H, 21-H), 0.9 (s, 3H, 18-H), 0.8 (s, 3H, 19-H) ppm.EIMS (m/z, %) 447 (M+1), 386 (10.55), 326 (78.61), 311 (62.63), 43 (100). ultimate analysis: (C 26H 38O 6) theoretical value, C%69.96, H%8.52
Measured value, C%69.89, H%7.97.
Embodiment 3:5 β-3 β-acetoxyl group-22-steroid acid-16-alcoholic lactone:
The acetic ester 10mmol of zhimusaponin unit (Sarsarsapogenin) is dissolved in the 50ml tetrahydrofuran (THF), stirs to add 0.1mmolBr down 2, 0-25 ℃, drip the solution of the 25mmol monoperphthalic acid magnesium of new system lentamente, stir after 1 hour, be warming up to 60 ℃, TLC tracks to raw material and disappears; Add the saturated pyrosulphite hydrogen of 15ml sodium solution in reaction flask, vigorous stirring is to the solution look, and 3 * 10ml tetrahydrofuran (THF) extracts, and merges organic phase, uses saturated NaHCO successively 3Wash, washing, saturated common salt is washed to neutrality, anhydrous MgSO 4Dried overnight concentrates, the contract crude product of ester cpds of 22-steroid acid-16-alcohol.Crude product is selected the appropriate solvent recrystallization for use, gets 5 β-3 β-acetoxyl group-22-steroid acid-16-alcoholic lactone.Yield: 86%.[α]=-30.82 ° (c, 0.36, CHCl 3) mp:190-192 ℃ IR (KBr) 2933,2866,1757,1735,1254,1026,987,972,518cm -1HNMR (300MHz, CDCl3) δ: 5.1, (m, 1H, 16-H), 4.9 (m, 1H, 16-H), 2.6 (m, 1H, 17-H), 2.2 (m, 1H, 20-H), 2.0 (s, 3H, CH 3CO-), 1.3 (d, J=7.0Hz, 3H, 21-H), 0.9 (s, 3H, 18-H), 0.7 (s, 3H, 19-H) ppmEIMS (m/z, %) 388 (M), 328 (100), 313 (89.77), 109 (44.15), 107 (45.49). ultimate analysis: (C 24H 36O 41/4H 2O) theoretical value, C%73.38, H%9.30
Measured value, C%73.19, H%9.40.
Embodiment 4:5 α-3 β-mesyloxy-6 α-acetoxyl group-22-steroid acid-16-alcoholic lactone 5 α-3 β-mesyloxy-6 α-acetoxyl group-steroid sapogenines 10mmol is dissolved in the 50ml methyl-sulphoxide, stir and add the 6mmol tetrabutylammonium iodide down, be chilled to 0 ℃, drip the solution of the adjacent formic acid benzoyl hydroperoxide of 1.5mol of new system lentamente, finish in the 30mins, continue to be incubated 0 ℃ of stirring after 1 hour, answer the chamber of being warming up to, and TLC tracks to raw material and disappears; Add the saturated sodium sulfite solution of 5ml in reaction flask, vigorous stirring is to solution look, 3 * 10mlCH 2Cl 2Extract, merge organic phase, use saturated NaHCO successively 3Wash, washing, saturated common salt is washed to neutrality, anhydrous MgSO 4Dried overnight concentrates, the contract crude product of ester cpds of 22-steroid acid-16-alcohol.The crude product recrystallization gets 5 α-3 β-mesyloxy-6 α-acetoxyl group-22-steroid acid-16-alcoholic lactone.Yield: 92%.[α]=-14.26 ° (c, 0.5, CHCl 3) mp:157-158 ℃ IR (KBr) 2939,2821,1767,1726,1476,1355,1177,935,869cm -1HNMR (300MHz, CDCl 3) δ: 4.9-5.0 (m, 1H, 16-H), 4.6-4.7, (m, 2H, 3-H, 6-H), 3.0 (s, 3H, CH3SO2-), 2.6 (m, 1H, 17-H), 2.2 (m, 1H, 20-H), 2.1 (s, 3H, CH 3CO-), 1.3 (d, J=7.0Hz, 3H, 21-H), 0.9 (s, 3H, 18-H), 0.7 (s, 3H, 19-H) ppm.EIMS (m/z, %) 407,326 (100), 311 (37.51), 147 (32.71), 107 (41.89), 91 (32.35) ultimate analyses: (C 25H 38O 7S) theoretical value, C%62.24, H%7.88
Measured value, C%62.39, H%8.39.
Embodiment 5:3 beta-acetoxyl group-5 α, 6 alpha-oxo-s-22-steroid acid-16-alcoholic lactone
Diosgenin (Diosgenin) acetic ester 10mmol is dissolved in 50ml N, in the dinethylformamide, stir and add the 6mmol magnesium bromide down, be chilled to 0 ℃, drip the solution of the adjacent formic acid benzoyl hydroperoxide of 1.5mol of new system lentamente, finish in the 30mins, continue to be incubated 0 ℃ of stirring after 1 hour, be warming up to the chamber and answer, TLC tracks to raw material and disappears; Add the saturated safety powder solution of 5ml in reaction flask, vigorous stirring is to solution look, 3 * 10mlCH 2Cl 2Extract, merge organic phase, use saturated NaHCO successively 3Wash, washing, saturated common salt is washed to neutrality, anhydrous MgSO 4Dried overnight concentrates, the contract crude product of ester cpds of 22-steroid acid-16-alcohol.The crude product recrystallization gets 5 (6)-epoxidised lactone-3 beta-acetoxyl group-5 α, 6 alpha-oxo-s-22-steroid acid-16-alcoholic lactone.Yield: 65%.[α]=10.48°(c,2.96,CHCl 3)mp：106-108℃IR?(KBr)2946,2877,1784,1735,1456,1383,967,880,736cm -1。HNMR?(300MHz,CDCl 3)δ：5.1(m,1H,3-H),4.9-5.0(m,1H,16-H),4.8(m,1H,6-H),2.6(m,1H,20-H),2.1(s,3H,CH 3CO-),1.1,(s,3H,18-H),0.7(s,3H,19-H)ppm。EIMS(m/z,％)?401(M-1),342(26.93),309(32.35),105(32.71),43(100)。
Embodiment 6:3 β, the 6 beta-acetoxyl group-5 alpha-hydroxy-2 2-steroid acid-16-alcohol ester that contracts
Figure 0012797400131
Do the peroxidation agent with peroxy tert-butyl alcohol, isopropyl ether is made polar solvent, and from 3 β, 6 beta-acetoxyl group-5 Alpha-hydroxy-steroid sapogeniness obtain corresponding 3 β with embodiment 1 operation for other, 6 beta-acetoxyl group-5 alpha-hydroxy-2 2-steroid acid-16-alcohol ester that contracts.Yield: 83%.[α]=-92.39 ° (c, 0.35, CHCl 3) mp:183-184 ℃ IR (KBr) 3487,2943,2876,2852,1773,1734,1456,1376,1183cm -1HNMR (300MHz, CDCl 3) δ: 5.1 (m, 1H, 3-H), 4.9 (m, 1H, 16-H), 4.7 (m, 1H, 6-H), 2.6 (m, 1H, 20-H), 2.1 (s, 3H, CH 3CO-), 2.0 (s, 3H, CH 3CO-), 1.1 (s, 3H, 18-H), 0.7 (s, 3H, 19-H) ppmEIMS (m/z, %) 420 (7.19), 359 (6.29), 342 (100), 327 (39.56), 43 (52.79) ultimate analyses: (C 26H 38O 71/8H 2O) theoretical value, C%67.20, H%8.24
Measured value, C%67.02, H%8.45.
Embodiment 7:3 β-acetoxyl group-12-ketone-22-steroid acid-16-alcoholic lactone
Do the peroxidation agent with peroxide sulfonic acid, other is operated with embodiment 1, and luxuriant numb sapogenin (Hecogenin) acetic ester of directly degrading is reflected at room temperature and carries out obtaining in 6 hours 3 β-acetoxyl group-12-ketone-22-steroid acid-16-alcoholic lactone as the principal reaction product.Yield: 71%.[α]=25.12 ° (c, 0.43, CHCl 3) mp:162-163 ℃ IR (KBr) 2945.7,2848.8,1773.5,1730.2,1704.2,1240.7,855.8,902.6cm -1HNMR (300MHz, CDCl3) δ: 4.9 (m, 1H, 16-H), 4.6 (m, 1H, 3-H), 1.4 (d, J=7.6Hz, 3H, 21-H), 1.1 (s, 3H, 18-H), 0.9 (s, 3H, 19-H) ppmEIMS (m/z, %) 402 (M, 4.56), 342 (100), 327 (19.47), 288 (48.49), 43 (32.98) ultimate analyses: (C 24H 34O 61/4H 2O) theoretical value, C%70.85, H%8.49
Measured value, C%70.54, H%8.64.
Embodiment 8:3 β-acetoxyl group-1 2-ketone-C-height-13-oxa--22-steroid acid-16-alcoholic lactone
Figure 0012797400141
With dibenzoyl peroxide as the peroxidation agent, other operation is with embodiment 1, directly degraded luxuriant numb sapogenin (Hecogenin) acetic ester is reflected at 60 ℃ and carries out obtaining in 48 hours as principal reaction product 3 β-acetoxyl group-12-ketone-C-height-13-oxa--22-steroid acid-16-alcoholic lactone.Yield: 92%[α]=-66.99 ° of (c, 0.3, CHCl 3) mp:178-180 ℃ IR (KBr) 2947.9,2850.7,1773.8,1730.0,1238.6,1023.9,1008.9,907.0cm -1HNMR (300MHz, CDCl3) δ: 4.90 (m, 1H, 16-H), 4.60 (m, 1H, 3-H), 2.0 (s, 3H, CH 3CO-), 1.4 (s, 3H, 18-H), 1.3 (d, J=7.6Hz, 3H, 21-H), 0.7 (s, 3H, 19-H) ppmEIMS (m/z, %) 419 (M+1), 401 (6.58), 341 (18.56), 264 (51.43), 204 (100), 43 (75). ultimate analysis: (C 24H 34O 6) theoretical value, C%68.90, H%8.13
Measured value, C%69.06, H%7.83.
Embodiment 9:3 beta-hydroxy-5-bromo-6 (19)-epoxies-22-steroid acid-16-alcoholic lactone
Figure 0012797400142
Obtain corresponding 3 beta-hydroxies-5-bromo-6 (19)-epoxies-22-steroid acid-16-alcoholic lactone with embodiment 1 operation from 3 beta-hydroxies-5-bromo-6 (19)-epoxies-steroid sapogenines.Yield: 85%.m.p.262-264℃IR(KBr)：ν?3416,3333(OH),1778,1741?cm -1(C=O)cm -1 1H-NMR(CDCl 3+CD 3OD)δ：5.03(1H,m,16-H),4.09(1H,d,J=3.9?Hz,6α-H),4.07(1H,m,3-H),3.98(1H,d,J=8.4?Hz,19-Ha),3.75(1H,d,J=8.4?Hz,19-Hb),2.62(1H,m,20-H),1.33(3H,d,J=7.6?Hz,21-CH 3),0.81(3H,s,18-CH 3)ppmEIMS：m/e?439(M+1),341(M-Br-OH),41(100％)。
Embodiment 10:3-oxo-19-methylol-Gao-steroid-4 alkene-22-acid-16-alcoholic lactone
Figure 0012797400151
At 0 ℃, use Jone ' s reagent oxidation 3 beta-hydroxies-5-bromo-6 (19)-epoxies-22-steroid acid-16-alcoholic lactone to obtain corresponding 3-oxo-19-methylol-Gao-steroid-4 alkene-22-acid-16-alcoholic lactone.Yield: 73%.M.p.208-209 ℃ [α] D 20=+54 (c 0.17, CHCl 3) IR (KBr): v 3446 (OH), 1770 (lactone C=O), 1662 (alpha, beta-unsaturated ketone C=O), 1617cm -1(C=C) cm -1 1H-NMR (CDCl 3) δ: 5.91 (1H, s, 4-H), 4.97 (1H, m, 16-H), 4.05 (1H, d, J=10.7 Hz, 19-Ha), 3.90 (1H, d, J=10.7 Hz, 19-Hb), 2.57 (1H, m, 20-H), 1.30 (3H, d, J=7.6 Hz, 21-CH 3), 0.78 (3H, s, 18-CH 3) .EIMS:m/e 358 (M), 328 (100%, M-CH 2O) ultimate analysis: theoretical value (%): C73.71 H8.44
Measured value (%): C73.15 H8.37.
Embodiment 11:3-oxo-10 (19)-methylene base-steroid-1-alkene-22-acid-16-alcoholic lactone
Figure 0012797400152
Rearrangement reaction (Chinese patent, application number: 97106575.6) obtain corresponding 3-oxo-10 (19)-methylene base-steroid-1-alkene-22-acid-16-alcoholic lactone that 3-oxo-19-methylol-Gao-steroid-4 alkene-22-acid-16-alcoholic lactone has been reported through us.React as follows: the 0.5mmol substrate is dissolved in 10-15ml solvent (dry toluene or anhydrous tetrahydro furan).Ice-water bath drips DBU and the 1-1.5eq.HCF of 1.5eq. down 2CF 2OCF 2CF 2SO 2F.Finish, reacted 0.5-2 hour.Through post, drip washing merges wash filtrate, adds the triethylamine of 5eq. with reaction solution, back flow reaction, and TLC follows the tracks of, and reaction finishes DBU and the 4.0eq.HCF that the back adds 4.0eq. 2CF 2OCF 2CF 2SO 2F, room temperature to 60 ℃ reaction, TLC follows the tracks of.Post, eluent solvent are crossed in the reaction back, merge washings and boil off solvent, and column chromatography for separation gets intermediate.Yield: 88%.M.p.162-164 ℃ [α] D 20=+65 (c 0.17, CHCl 3) IR (KBr): ν 1758 (lactone C=O), 1671 (alpha, beta-unsaturated ketone C=O), 1608 cm -1(C=C) cm -1 1H-NMR (CDCl 3) δ: 7.27 (1H, d, J=10.3 Hz, 1-H), 5.74 (1H, d, J=10.2 Hz, 2-H), 4.94 (1H, m, 16-H), 2.84 (1H, d .J=18.5 Hz, 4-Ha), 2.46 (1H, d, J=18.5 Hz, 4-Hb), 1.30 (3H, d, J=7.6 Hz, 21-CH 3) 1.15 (1H, d, J=4.4Hz, 19-Ha), 0.77 (3H, s, 18-CH 3), 0.32 (1H, d .J=4.3 Hz, 19-Hb) EIMS:m/e 340 (M), 91 (100%) ultimate analyses: theoretical value (%): C77.61, H8.29
Measured value (%): C77.32, H8.43.
Embodiment 12:3-(5H-3-oxo octafluoro pentyl sulfonyloxy)-10 (19)-methylene bases-5 (10)-disconnected-steroid-1 (10), 2,4-triolefin-22-acid-16-alcoholic lactone:
Rearrangement reaction (the Chinese patent that 3-oxo-19-methylol-Gao-steroid-4 alkene-22-acid-16-alcoholic lactone has been reported through us, application number: 97106576.4) obtain corresponding 3-(5H-3-oxo octafluoro pentyl sulfonyloxy)-10 (19)-methylene bases-5 (10)-disconnected-steroid-1 (10), 2,4-triolefin-22-acid-16-alcoholic lactone.React as follows: the 0.5mmol substrate is dissolved in 10-15ml organic solvent (dry toluene or anhydrous tetrahydro furan).Ice-water bath drips DBU and the 2-5eq.HCF of 1.5eq. down 2CF 2OCF 2CF 2SO 2F.Finish, reacted 0.5-2 hour.Through post, drip washing merges wash filtrate, adds the triethylamine of 5eq. with reaction solution, back flow reaction, and TLC follows the tracks of, and reaction finishes DBU and the 4.0eq.HCF that the back adds 4.0eq. 2CF 2OCF 2CF 2SO 2F, room temperature to 60 ℃ reaction, TLC follows the tracks of.Post, eluent solvent are crossed in the reaction back, merge washings and boil off solvent, and column chromatography for separation gets intermediate.Yield: 88%.M.p.127-128 ℃ [α] D 20=+50 (c 0.19, CHCl 3) IR (KBr): ν 1761 (lactone C=O), 1594 cm -1(cycloheptatriene C=C) cm -1 1H-NMR (CDCl 3) δ: 6.69 (1H, d, J=6.0 Hz, 1-H), 6.06 (1H, d, J=6.4 Hz, 2-H), 6.02 (1H, s, 4-H), 5.86 (1H, tt, J=52.5 Hz and 3.1 Hz, HCF 2CF 2), 4.94 (1H, m, 16-H), 3.41 (1H, d, J=10.3 Hz, 19-Ha), 2.62 (1H, m, 20-H), 1.33 (3H, d, J=7.6 Hz, 21-CH3), 0.93 (3H, s, 18-CH 3), 0.86 (1H, d, J=10.4 Hz, 19-Hb) EIMS:m/e 622 (M+2), 145 (100%).Ultimate analysis: theoretical value (%): C50.32, H4.55
Measured value (%): C50.44, H4.51.
Embodiment 13:
3 β, 12 β-bi-methoxy methyl-hydroxy-16 alpha--hydroxyl-22-steroid acid-16-alcoholic lactone
Under nitrogen protection, will be by 3 β, 12 β-acetoxyl group-16 alpha-hydroxy-2 2-steroid, 3 β that acid-the 16-alcoholic lactone obtains after conventional hydrolysis, 12 beta-hydroxies-16 alpha-hydroxy-2 2-steroid acid-16-alcoholic lactone is got 4.24g, 15gP 2O 5, join the anhydrous CHCl of 50ml 3In, stirring and dissolving adds 21ml (CH 3O) 2CH 2, room temperature-60 ℃ stirring, TLC tracks to reaction to be finished.With CHCl 3Solution is to going into to the NaHCO of ice 3In the saturated solution, branch vibration layer, organic phase is used saturated NaHCO successively 3Solution, saturated common salt water washing, drying concentrates, and column chromatography gets compound 4.713g.
Figure 0012797400162
IR (KBr): ν 3377 (hydroxyl), 1747 (lactone C=O) cm -1 1H-NMR (CDCl 3) δ: 4.70 (1H, d, J=7.68Hz ,-OCH 2O-), 4.68 (2H, s ,-OCH 2O-), 4.59 (1H, d, J=7.68Hz ,-OCH 2O-), 3.46 (1H, m, 3-H), 3.37 (6H, s, 2 x-OCH 3), 1.41 (1H, d, J=7.68Hz, 21-CH 3), 0.83 (3H, s, 18-CH 3), 0.76 (3H, s, 19-CH 3) ppmEIMS:m/e 448 (M +-H 2O), 404 (M +-2CH 3O), 45 (CH 3OCH +).
Embodiment 14:3 β, 12 β-bi-methoxy methyl-22-steroid acid-16-alcoholic lactone
5 α-3 β after 12 β-acetoxyl group-22-steroid acid-acetic ester is removed in the reaction of 16-alcoholic lactone process routine hydrolysis, obtains 3 β, 12 β-bi-methoxy methyl-22-steroid acid-16-alcoholic lactone with the reaction of chloromethyl methyl ether again.Ether reaction is in the solvent of ether such as ether, glycol dimethyl ether or tetrahydrofuran (THF), the mol ratio of substrate, chloromethyl methyl ether and sodium hydride is 1: 2-5: 0.001-1, room temperature reaction 2-20 hour or 0.5 hour IR (KBr): ν 1758 (lactone C=O) cm of 60 ℃ of reactions -1 1H-NMR (CDCl 3) δ: 4.94 (1H, m, 16-H), 4.71 (1H, d, J=6.63Hz ,-OCH 2O-), 4.68 (2H, s ,-OCH 2O-), 4.58 (1H, d, J=6.63Hz ,-OCH 2O-), 3.49 (1H, m, 3-H), 3.37 (6H, s, 2x-OCH 3), 3.29 (1H, dd, J=11.1,4.6Hz, 12-H), 1.32 (1H, d, J=7.64Hz, 21-CH 3), 0.87 (3H, s, 18-CH 3), 0.84 (3H, s, 19-CH 3) ppm.EIMS：m/e?451(M ++1),45(CH 3OCH +)
Embodiment 15:3 β, 12 β-bi-methoxy methyl-17 Alpha-hydroxy-22-steroid acid-16-alcoholic lactone
Do the peroxidation agent with a halogen benzoyl hydroperoxide, obtain 3 β, 12 β-bi-methoxy methyl-17 Alpha-hydroxy-22-steroid acid-16-alcoholic lactone from noisy sapogenin (Pennogenin) degraded of the spray of protection with embodiment 1 operation.IR (KBr): v3415 (hydroxyl), 1758 (lactone C=O) 3011 (HC=CH) cm -1 1H-NMR (CDCl 3): δ 7.3 (m, 5H, Ar-H), 4.9 (m, 1H, 16-H), 4,8 (m, 1H, 6-H), 4.4 (s, 2H, Ar-CH 2-), 4.58 (1H, dd, J=7.8,4.65Hz, 16-H), 3.53 (1H, m, 3-H), 1.28 (1H, d, J=7.9Hz, 21-CH 3), 0.93 (3H, s, 18-CH 3), 0.87 (3H, s, 19-CH 3) ppmEIMS (m/z, %) 622 (M +), 604,588,542,524,478,336,289,91 (100), 43 (25.17)
Embodiment 16:3 β-benzyloxy-5 α, 6 beta-2-dibroms-22-steroid acid-16-alcoholic lactone
Figure 0012797400181
With embodiment 1 operation, obtain corresponding 3 β-benzyloxy-5 α, 6 beta-2-dibroms-22-steroid acid-16-alcoholic lactone from the degraded of two bromo diosgenin (Diosgenin) acetic ester.IR (KBr): v 3415 (hydroxyl), 3011 (HC=CH), 1758 (lactone C=O) cm -1 1HNMR (300MHz, CDCl 3) δ: 7.3 (m, 5H, Ar-H), 4.9 (m, 1H, 16-H), 4,8 (m, 1H, 6-H), 4.4 (s, 2H, Ar-CH 2-), 2.6 (m, 1H, 17-H), 1.3 (d, J=8.8Hz, 3H, 21-H), 0.9 (s, 3H, 18-H), 0.7 (s, 3H, 19-H) ppmEIMS (m/z, %) 606 (M +), 588,524,478,336,289,91,43.
Embodiment 17:3 β-benzyloxy-5-alkene-22-steroid acid-16-alcoholic lactone
Figure 0012797400182
3 β-benzyloxy-5 α, 6 beta-2-dibroms-22-steroid acid-16-alcoholic lactone and zinc powder generation debromination obtain corresponding 3 β-benzyloxy-5-alkene-22-steroid acid-16-alcoholic lactone.Typical operation is to add 12g 3 β-benzyloxy-5 α, 6 beta-2-dibroms-22-steroid acid-16-alcoholic lactone, 1.8gNH in organic solvents such as 50-400ml ethanol 4Cl, the 0.8-4.3g zinc powder, heating reflux reaction 0.5-40 hour, aftertreatment got 3 β-benzyloxy-5-alkene-22-steroid acid-16-alcoholic lactone.[α] D 20=-23.4 ° of (c=0.68, CHCl 3) (KBr): ν 3415 (hydroxyl), 3011 (HC=CH), 1758 (lactone C=O) cm -1IR3001,2997,1735,1608,1405,1276,828,765cm -1 1HNMR (300MHz, CDCl 3) δ: 7.3 (m, 5H, Ar-H), 5.2 (m, 1H, 6-H), 4.9 (m, 1H, 16-H), 4.4 (s, 2H, Ar-CH 2-), 2.6 (m, 1H, 17-H), 1.2 (d, J=8.8Hz, 3H, 21-H), 1.0 (s, 3H, 18-H), 0.7 (s, 3H, 19-H) ppmEIMS (m/z, %) 448 (M +), 356 (46.13), 324 (7.88), 288 (12.54), 91 (100), 45 (8.48); Ultimate analysis: (C 29H 38O 3) calculated value: C%, 80.19, H%8.75;
Measured value: C%, 79.95, H%8.90
Embodiment 18:3 β-acetoxyl group-12-oxo-5-steroid-14 (15)-alkene-22-acid-16-alcoholic lactone
Figure 0012797400183
3 β-acetoxyl group-12-ketone-22-steroid acid-16-alcoholic lactone reference literature method transforms into 3 β-acetoxyl group-12-oxo-5-steroid-14 (15)-alkene-22-acid-16-alcoholic lactone through photochmeical reaction and oxidizing reaction.Concrete steps are the steroidal lactones that obtain obtaining in 0.5-10 hour the 12-hydroxyl earlier through high voltage mercury lamp radiation, obtain product through the Jones reagent oxidation again.Yield: 71%.IR(KBr)2945,2848.,1773,1730,1704,1240,855,902cm -1HNMR(300MHz,CDCl 3)δ：5.48(brs,1H,15-H)5.0(m,1H,16-H),4.,4.6(m,1H,3-H),2.5(m,1H,17-H),2.2(m,1H,20-H),2.1(s,3H,CH 3CO-),1.2(d,J=4.0Hz,3H,21-H),0.9(s,3H,18-H),0.8(s,3H,19-H)ppm.EIMS(m/z,％)358(M +),302(100),327,288,43.
Embodiment 19 3 (R)-methyl-gamma-butyrolactone
Figure 0012797400191
10 gram sisalagenin acetic ester (TicogeninAcetate) directly add 10 gram sodium bisulfites after (22mmol) degrading fully with the method for embodiment in reaction flask, vigorous stirring, and placement is spent the night.Organic phase concentrates.Rapid column chromatography obtains steroidal product 6.5 grams.Column chromatography liquid concentrates once more being lower than under 40 ℃ the water temperature, obtains the high boiling liquid product of about 2 grams, adds about 10mlHMPA as solvent in this liquid, and underpressure distillation obtains 920mg, yield: 42%.IR(KBr)2971,1780,1460,1422,1242,1174,1018,838,601,499cmHNMR(300MHz,CDCl3)δ：4.40(dd,J=8.7Hz,J=6.6Hz,1H,4-H),3.80(dd,J=8.8Hz,J=6.4Hz,1H,4-H),2.60(dd,J=20Hz,J=10.4Hz,1H,2-H),2.2(dd,J=21HzJ=10.2Hz,1H,2-H),2.60(t,1H,3-H),1.2(d,J=11.2Hz,-CH3)ppm。EIMS(m/z,％)101(M+1,100),83(9.96),71(1.52),56(30.80),50(1.03),41(63.65)。

Claims (10)

1. lactone compound has following general molecular formula:
Figure 0012797400021
, in the formula, during M=H, Y=
Figure 0012797400022
During the M=Alpha-Methyl, Y has following molecular formula:
Figure 0012797400023
Among the Y, n or m=0 or 1, the p=singly-bound or-O-, R 1=H is perhaps with R 2Or R 10Be connected to two keys of A ring; R 2=H is perhaps with R 1Or R 3Be connected to two keys of A ring; R 3=H, OH ,=O, CH 3O, CH 3COO, CH 3OCH 2O, C 6H 5COO, C 6H 5CH 2O, R fSO 3, perhaps with R 2Be connected to two keys of A ring, wherein R f=HCF 2CF 2OCF 2CF 2, CF 3(CF 2) 7, CF 3(CF 2) 3, CF 3Or CH 3OOCCF 2
R 4=H is perhaps with R 5Be connected to two keys of A ring;
R 5=H, X, OH are perhaps with R 4Or R 6Be connected to two keys of A ring or B ring, perhaps with R 6Be connected to-O-;
R 6=H, OH, X, CH 3COO is perhaps with R 1Be connected to-CH 2-O-is perhaps with R 5Be connected to two keys of B ring, perhaps with R 5Be connected to-O-, perhaps with R 10Be connected to-CH 2-O-, wherein X=F, Cl, Br or I;
R 10=H, CH 3, CH 2OH is perhaps with R 6Be connected to-CH 2-O-;
R 12=H ,=O, CH 3COO or CH 3OCH 2O;
R 13=H、CH 3、OH、CH 3COO；
R 14And R 15=H or be connected to two keys on the D ring;
R 16Or R 17=H or OH;
The valence mumber of carbon is 4 in the above-mentioned molecular formula, and works as R 1, R 2, R 4, R 5, R 6, R 9, R 11, R 12, R 14, R 15, R 16And R 17All=H, and R 10And R 13=CH 3The time, R 3≠ CH 3COO.
2. lactone compound as claimed in claim 1 is characterized in that among the above-mentioned molecular formula Y
Figure 0012797400024
Figure 0012797400025
R in the formula 1, R 2, R 3, R 4, R 5, R 6And R 10Definition and the restriction according to claim 1.
3. lactone compound as claimed in claim 1 is characterized in that among the above-mentioned molecular formula Y
Figure 0012797400032
Figure 0012797400033
R in the formula 12, R 13, R 14, R 15, R 16And R 17Definition and the restriction according to claim 1.
4. the synthetic method of lactone compound as claimed in claim 1, this lactone compound has following general molecular formula:
Figure 0012797400034
In the formula, during M=H, Y=
Figure 0012797400035
During the M=Alpha-Methyl, Y has following molecular formula:
Figure 0012797400036
Among the Y, n or m=0 or 1; The p=singly-bound or-O-; R 1=H is perhaps with R 2Or R 10Be connected to two keys of A ring; R 2=H is perhaps with R 1Or R 3Be connected to two keys of A ring; R 3=H, OH ,=O, CH 3O, CH 3COO, CH 3OCH 2O, C 6H 5COO, C 6H 5CH 2O, R fSO 3, perhaps with R 2Be connected to two keys of A ring, wherein R f=HCF 2CF 2OCF 2CF 2, CF 3(CF 2) 7, CF 3(CF 2) 3, CF 3Or CH 3OOCCF 2
R 4=H is perhaps with R 5Be connected to two keys of A ring;
R 5=H, X, OH are perhaps with R 4Or R 6Be connected to two keys of A ring or B ring, perhaps with R 6Be connected to-O-;
R 6=H, OH, X, CH 3COO is perhaps with R 1Be connected to-CH 2-O-is perhaps with R 5Be connected to two keys of B ring, perhaps with R 5Be connected to-O-, perhaps with R 10Be connected to-CH 2-O-, wherein X=F, Cl, Br or I;
R 10=H, CH 3, CH 2OH is perhaps with R 6Be connected to-CH 2-O-;
R 12=H ,=O, CH 3COO or CH 3OCH 2O;
R 13=H、CH 3、OH、CH 3COO；
R 14And R 15=H or be connected to two keys on the D ring;
R 16Or R 17=H or OH;
The valence mumber of carbon is 4 in the above-mentioned molecular formula;
It is characterized in that comprising the steps 1) or step 1) and 2): 1) in polar solvent and 0-60 ℃ the time, the mol ratio of organic oxidizing agent, steroid sapogenines and reaction additives is 1.0-2.5: 1: 0.0005-1, reacted 5-40 hour, obtain steroidal lactone compound and 3 (R)-methyl-gamma-butyrolactone, described reaction additives is the organic salt of bromine, iodine, bromine or iodine or the organic salt of bromine or iodine.2) with 1) arbitrary step or a few step reaction of gained steroidal lactone compound in conventional hydrolysis, Jone ' s reagent oxidation, Huang Min-lon reduction, ether reaction, the dehalogenation reaction, photochemical/oxidizing reaction or the rearrangement reaction.
5. the synthetic method of lactone compound as claimed in claim 4, it is characterized in that described steroid sapogenines is to comprise diosgenin (Diosgenin), sisalagenin (Tigogenin), zhimusaponin unit (Sarsarsapogenin), the noisy sapogenin (pennogenin) of spray, rockogenin (Rocogenin), luxuriant numb sapogenin (Hecogenin), 5 α-3 β-mesyloxy-6 α-acetoxyl group-steroid sapogenines, 3 β, 6 beta-acetoxyl group-5 Alpha-hydroxy-steroid sapogeniness, 3 beta-hydroxies-5-bromo-6 (19)-epoxies-steroid sapogenines and their acetic ester are at the interior natural sapogenin and the modifier of natural sapogenin.
6. the synthetic method of lactone compound as claimed in claim 4, it is characterized in that described organic oxidizing agent is to comprise peroxy trifluoroacetic acid, Peracetic Acid, benzoyl hydroperoxide, between the halogen benzoyl hydroperoxide, adjacent formic acid benzoyl hydroperoxide, single peroxy maleic acid, the magnesium salts of monoperphthalic acid, the benzoyl hydroperoxide that nitro replaces, dibenzoyl peroxide, peroxy tert-butyl alcohol, peroxide sulfonic acid is at the organic oxidation reagent of interior fat and fragrance.
7. the synthetic method of lactone compound as claimed in claim 4, it is characterized in that described polar solvent is to comprise methylene halide, haloform, tetrahydrofuran (THF), methyl-sulphoxide, N, dinethylformamide, low carbon chain ether, low carbon chain alcohol are at interior proton or aprotic polar solvent.
8. the synthetic method of lactone compound as claimed in claim 4 is characterized in that described rearrangement reaction is in the time of organic solvent neutralization-5-30 ℃, substrate, sulfonated reagent R fSO 2The mol ratio of F and alkali is 1: 1-10: 2-20, reacted 5-24 hour, wherein R fAs described in claim 1 or 4, alkali comprises pyridine, 2,6-lutidine, N (CH 3) 3, [(CH 3) 2CH] 2NH, Na 2CO 3, NaH, (CH 3) 3COK, NaOH, KOH, NH 3, 1,5-diazabicyclo [4.3.0] nonane-5-alkene, 1,8-diazabicyclo [5.4.0] undecane-7-alkene and (C 4H 9) 4NF.
9. the purposes of lactone compound as claimed in claim 1 is characterized in that comprising 22-steroid aldehyde as synthetic, the acid of 22-steroid, and the 16-sterol, 16-steroid alkene, 15-steroid alkene is at interior steroidal compounds and the precursor that contains the compound of chirality methyl side chain.
10. as the purposes of claim 1 or 8 described lactone compounds, it is characterized in that having active natural steroid molecule and steroid drugs as synthesizing.
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WO2005007668A1 (en) * 2003-07-16 2005-01-27 Shanhghai Institute Of Organic Chemistry, Chinese Academy Of Sciences A production process for 16-dehydropregnenoneol and its analogs
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CN101003561B (en) * 2007-01-19 2011-01-05 中国科学院上海有机化学研究所 Polyhydroxyl steroid compound, synthetic method, and application
CN103588693A (en) * 2013-10-14 2014-02-19 青岛文创科技有限公司 Preparation method of trifluoroperacetic acid
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CN112979742A (en) * 2021-03-01 2021-06-18 泰州职业技术学院 3 alpha, 20, 20-trihydroxy-5 alpha-pregna-18-carboxylic acid-gamma-lactone and preparation method thereof
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