CN101195650A - Process of stereospecific synthesis of sapogenins - Google Patents
Process of stereospecific synthesis of sapogenins Download PDFInfo
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- CN101195650A CN101195650A CNA2007101699386A CN200710169938A CN101195650A CN 101195650 A CN101195650 A CN 101195650A CN A2007101699386 A CNA2007101699386 A CN A2007101699386A CN 200710169938 A CN200710169938 A CN 200710169938A CN 101195650 A CN101195650 A CN 101195650A
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Abstract
A method to stereospecifically prepare a steroidal sapogenin or a derivative thereof by reducing a 3-keto,5beta-H steroidal sapogenin with a hindered organoborane or an organo-aluminium hydride. A 3beta-hydroxy,5beta-H steroidal sapogenin or derivative thereof may be prepared by reducing the 3-keto,5beta-H steroidal sapogenin using as reducing agent a relatively highly hindered organoborane reagent or by SN 2 inversion of a 3alpha-hydroxy,5beta-H steroidal sapogenin or derivative thereof. The organo-aluminium hydride may be used to prepare a 3alpha,5beta-H steroidal sapogenin or derivative thereof. The invention provides a convenient route to useful steroidal sapogenins such as sarsasapogenin, episarsasapogenin, smilagenin, epismilagenin and esters thereof, from readily available or easily preparable starting materials (e.g. diosgenone, preparable from diosgenin).
Description
The application divides an application, the international application no of its original application is PCT/GB2003/001780, international filing date is on April 28th, 2003, the China national application number is 03824744.5, the date that enters China is on April 28th, 2005, and denomination of invention is " the stereotaxis method of reducing of Saponin/TSM-3-ketone ".
Technical field
The present invention relates to the stereotaxis synthetic method of sapogenin.
Background technology
Someone once pointed out, some sapogenin and their derivative are (more particularly, the sapogenin that contains 5 β hydrogen atoms, especially the compound that contains 3-hydroxyl and 5 β hydrogen atoms can be used for treating illnesss such as cognitive disorder as chinaroot greenbrier sapogenin (sarsasapogenin), table chinaroot greenbrier sapogenin (episarsasapogenin), different chinaroot greenbrier sapogenin (smilagenin) and the different chinaroot greenbrier sapogenin of table (epismilagenin).Referring to for example WO 99/48482, WO99/48507, WO 01/49703, WO 02/079221 and WO 01/23406, the disclosure of above specification sheets all is incorporated herein with the form of reference to this active description.Formerly the synoptic diagram that provides of publication is identical to be used to name the synoptic diagram of described ring system and carbon atom position and these among the present invention.
The synthetic method of 3-hydroxy steroids and 3-hydroxyl steroid sapogenin has been described in the document.For example, by using sodium borohydride or the lithium aluminium hydride of use in diethyl ether in tetrahydrofuran (THF) and methyl alcohol, implemented from the method (Helv.Chim.Acta, 66,192-217 (1983)) of synthetic 3 beta-hydroxies of corresponding 3-ketone-5 α-H steroide-5 α-H steroide.
The patent No. is 3,875,195 (1975) United States Patent (USP) (its disclosure is incorporated herein with the form of reference) has been described the method that with Raney Ni (Raney nickel) and hydrogen 3-ketone-5 β-H steroide is catalysed and reduced into 3 beta-hydroxies-5 β-H steroide under pressurized conditions in the low-grade carboxylic acid.Its researchist points out, your Lay reduction reaction (MPV) has obtained the mixture that 3 Alpha-hydroxy steroides and 3 beta-hydroxy steroides exist with equal proportion through Meerwein-Pang doffer-river in Shangdong Province.It is reported that this mixture is difficult to separate.
At first introduced the height that often the is called Selectrides trialkyl hydroborons series reductive agent (people such as Brown that is obstructed in early days in the 1970's, J.Am.Chem.Soc.94,7159-7161 (1972), from then on, a large amount of publications occurred, wherein mentioned these reductive agents are applied in the synthetic method of some sterol.For example, at Steriods, 36,299-303 (1980); Steriods, 45,39-51 (1985); J.Chem.Soc.Commun.1239-1240 (1982); Tetrahedron, 40,851-854 (1984); Helv.Chim.Acta, 66,192-217 (1983); United States Patent (USP) the 6th, 150, No. 336 (2000); And Tetrahedron, 45, among the 3717-3730 (1989) (above disclosure all is incorporated herein with the form of reference), addressing specific 3-ketone-5 'beta ' steroids and 3-ketone-5 α steroide is corresponding 3 beta-hydroxies through the stereotaxis selective reduction, 5 β-H sterol and 3 Alpha-hydroxies, 5 α-H sterol.
About the steroid sapogenin, addressed the synthetic method of different chinaroot greenbrier sapogenin in the prior art: in Virahol, obtain with isopropoxy aluminium reducing chinaroot greenbrier ketone, be MPV reduction reaction (people such as Marker, J.Amer.Chem.Soc., 62,2525 (1940)).Marker once reported, the mixture (Marker and Rohrmann, J.Amer.Chem.Soc., 61,943 (1939)) that the product that chinaroot greenbrier Saponin/TSM ketone generation MPV reduction reaction generates is made up of chinaroot greenbrier sapogenin and table chinaroot greenbrier sapogenin.Disclosure in these publications all is incorporated herein with the form of reference.
Prior art had also once been reported some catalytic hydrogenation reaction, object lesson is the preparation method that the smart ketone of the cautious announcement of usefulness (tigogenone) of Blunden report makes table tigogenin (epitigogenin), this method is in the Glacial acetic acid that contains 2% hydrochloric acid, use Adams'catalyst (platinum oxide (IV)) to make the smart ketone generation of cautious announcement hydrogenation reaction prepare table tigogenin (J.Nat.Prod.42,478-482 (1979); Onderstepoort J.Vet.Res., 61,351-359 (1994)).Marker once reported the method (Marker and Rohrmann, J.Amer.Chem.Soc., 61,943 (1939)) that makes chinaroot greenbrier Saponin/TSM ketone generation hydrogenization acquisition table chinaroot greenbrier sapogenin in ethanol with Adams'catalyst.Prior art was also once reported the reductive action of sodium borohydride, its object lesson be Miles report make the preparation method (J.Agric.Food Chem., 41,914-917 (1993)) of table chinaroot greenbrier sapogenin from chinaroot greenbrier Saponin/TSM ketone with sodium borohydride.Prior art was also once reported the reductive action of over hydrogenation lithium aluminium, its object lesson be Djerassi report make the preparation method (J.Am.Chem.Soc. of the different chinaroot greenbrier sapogenin of table from different chinaroot greenbrier Saponin/TSM ketone, 74,422-424, (1952)), and Lajis report make the preparation method (Steroids, 58,387-389 (1993)) of table chinaroot greenbrier sapogenin from chinaroot greenbrier Saponin/TSM ketone.Disclosure in these publications all is incorporated herein with the form of reference.
United States Patent (USP) the 5th, 703, No. 052 (1997), the 5th, 807,834 (1998) and the 5th, 939, No. 398 (1999) (its disclosure all is incorporated herein with the form of reference) reported the synthetic method of using K-Selectride to produce 3 Alpha-hydroxies-5 α-H sapogenin at low temperatures.
In the embodiment 6 of WO 02/079221 (on October 10th, 2002 is open), addressed the method for three tert.-butoxy lithium aluminium hydride reduction chinaroot greenbrier Saponin/TSM ketone of using with synthetic table chinaroot greenbrier sapogenin.But this publication is not all to belong to prior art at All Countries.
The present invention is devoted to provide a kind of stereotaxis preferably to synthesize the method for 3-hydroxyl-5 β-H steroid sapogenin, described 3-hydroxyl-5 β-H steroid sapogenin is more preferably 3 beta-hydroxies-5 β-H sapogenin and their derivative that institute defines and describes among above-mentioned WO99/48482, WO 99/48507, WO 01/49703, WO 02,/07,922 1 and the WO 01/23406, such as corresponding saponins that can be used as prodrug and acceptable form on other physiology such as salt and ester class for example.
In the most preferred embodiment, the present invention is devoted to provide a kind of synthetic method of stereotaxis efficiently of synthetic following material: chinaroot greenbrier sapogenin, different chinaroot greenbrier sapogenin, table chinaroot greenbrier sapogenin, the different chinaroot greenbrier sapogenin of table and their prodrug, and acceptable form on other physiology.
Summary of the invention
In a first aspect of the present invention, provide a kind of stereotaxis to prepare the method for 3-hydroxyl-5 β-H steroid sapogenin or derivatives thereof, this method comprises uses reductive agent to reduce the step of 3-ketone-5 β-H steroid sapogenin, and employed reductive agent comprises be obstructed organo-borane or organoaluminum hydride.
Earlier obtain 3-hydroxyl-5 β-H steroid sapogenin by above-mentioned stereotaxis method of reducing, for example can utilizing subsequently, the known derivatize technology of prior art is translated into required derivative form.Above-mentioned conversion process can be carried out or carry out in different reaction systems on the spot, and can carry out simultaneously with described reduction reaction or carry out after described reduction reaction.
" organo-borane is obstructed " speech used herein refers in particular to trialkyl alkali metal borohydride reductive agent or triaryl alkali metal borohydride reductive agent, as: 3-sec-butyl lithium borohydride, three amyl group lithium borohydrides or triphenyl-boron lithium hydride, or the corresponding reductive agent of lithium after being replaced by potassium or sodium.Described alkyl preferably comprises 1～7 carbon atom, further preferably comprises 3～7 carbon atoms.Described aryl preferably comprises 6～12 carbon atoms, and can have alkyl as substituting group.These reductive agents are collectively referred to as " Selectride " reductive agent sometimes, but, here using term " Selectride " is not can only obtain reductive agent from any particular manufacturer or source place in order to limit the invention to, should be understood that, all can use from this type of reductive agent in any manufacturers and source place." reductive action of alanate and hydroborate in the organic synthesis (the Reductions by the Alumino-and Borohydrides inOrganic Synthesis) " that more detailed discussion can be write with reference to J.Seyden-Penne (VCH publishing company).The preferred 3-sec-butyl lithium borohydride of the organo-borane that is obstructed (L-Selectride) of Shi Yonging, three sec-butyl POTASSIUM BOROHYDRIDE (K-Selectride), three sec-butyl sodium borohydrides (N-Selectride), three amyl group lithium borohydrides (LS-Selectride), three amyl group POTASSIUM BOROHYDRIDE (KS-Selectride), triphenyl-boron potassium hydride KH and triphenyl-boron lithium hydride in the present invention.
In the present invention, " organoaluminum hydride " refers in particular to any aluminium and hydride part and organic group of comprising (as alkyl or alkoxyl group, the alkyl or the alkoxyl group that preferably comprise 1～7 carbon atom) reductive agent, as two-(2-methoxy ethoxy) sodium alanates (Red-Al ), diisobutyl alanate (DIBAL) or three tert.-butoxy aluminium lithium hydrides (LTBA).More detailed discussion can be with reference to " reductive action of alanate and hydroborate in the organic synthesis " of being write by J.Seyden-Penne (VCH publishing company).The preferred in the present invention organoaluminum hydride that uses is Red-Al, DIBAL and LTBA.
In the present invention, " derivative " speech relevant with sapogenin refers in particular to the corresponding Saponin/TSM that can be used as prodrug and for example acceptable form on other physiology such as salt and ester.Change between sapogenin and its derivative is easy to be undertaken by well-known reaction in the prior art.The derivative form of sapogenin can be with deriveding group on one or more positions of molecule.For example, Saponin/TSM and its ester derivative can carry deriveding group on 3 of A ring.This is expressed in the derivative form that this has comprised that they are all " sapogenin ", unless can obviously draw opposite conclusion from context.
" derivative " speech that is associated with a third aspect of the present invention (will in subsequent discussion) is the reactive derivative that refers in particular to sapogenin, and this derivative is useful in this reaction.
By selecting appropriate reductant for use, present method with higher or high overall yield (for example can be utilized starting raw material commercially available or that be easy to prepare, be approximately higher than 80% transformation efficiency) a series of 3 Alpha-hydroxies of preparation, 5 β-H sapogenin and 3 beta-hydroxies, 5 β-H sapogenin and their derivative, the product that is obtained are substantial pure state or are at least based on the pure form of stereoisomerism.This method can avoid the bigger isomer mixture of difficulty to separate usually.
Before the present invention, will not be obstructed organo-borane or organoaluminum hydride reducer are used to reduce 3-ketone-5 β-H steroid sapogenin.The Miles preparation method of table smilacin aglucon (is seen J.Agric.Food Chem, 41,914-917 (1993)) (its disclosure is incorporated herein with the form of reference) uses sodium borohydride as reductive agent, although when reporting this research work, better reagent LTBA is well known for selectivity.
When reductive agent was the high relatively organo-borane that is obstructed (carbonatoms of organic group is greater than about 2), the sapogenin that obtains should mainly be 3 beta-hydroxies, 5 β-H sapogenin.
When reductive agent is the low relatively organo-borane that is obstructed when (carbonatoms of organic group is about 2 at most), the sapogenin that obtains should mainly be 3 Alpha-hydroxies, 5 β-H sapogenin.
When reductive agent was organoaluminum hydride, the sapogenin that obtains should mainly be 3 Alpha-hydroxies, 5 β-H sapogenin.
At this; use 3-ketone; 5 β-this statement of H sapogenin is for convenience's sake; it refers to the starting raw material that is used for reduction reaction; but might not mean that other parts at molecule (as beyond the A ring) are all saturated or do not have ketone group to exist; if necessary, as long as any unwanted active site that other parts exist in the due care molecule.Starting raw material 3-ketone, 5 β-H sapogenin and required final product can be in molecule a plurality of positions except that 3 of A ring different; At this moment, should adopt mode well-known to those skilled in the art to carry out necessary conversion, with a this part that transforms as the complete synthesis route that obtains required final product.
Starting raw material 3-ketone, 5 β-H steroid sapogenin can obtain by the corresponding 3-hydroxyl of oxidation sapogenin.For example, as described in Miles, carry out oxidation by pyridinium dichromate and made chinaroot greenbrier Saponin/TSM ketone (J.Agric Food Chem., 41,914-917 (1993)); Perhaps adopt the Jones oxidizing reaction described in Blunden (J.Nat.Prod., 42,478-482 (1979)) and the WO-98/07741 to make chinaroot greenbrier Saponin/TSM ketone; Above disclosure all is incorporated herein with the form of reference.Utilize α, the reduction reaction of two keys of beta unsaturated ketone makes different chinaroot greenbrier Saponin/TSM ketone (people such as Marker, J.Am.Chem.Soc.2525 (1940), Irismetov ﹠amp by dioscin ketone (itself obtained by the diosgenin oxidation); Goryaev, Izv.Akad.Nauk Kaz.SSR, Ser.Khim., 2,47-52 (1981)).
A preferred specific embodiments of the present invention is: starting raw material 3-ketone, 5 β-H steroid sapogenin can be by corresponding Δ
4, 3-ketone steroid sapogenin (as dioscin ketone) is by the preparation of heterogeneous catalytic hydrogenation process.Heterogeneous catalytic hydrogenation makes Δ
4, 3-ketone steroid sapogenin mainly is converted into corresponding 5 β-H3-ketone product, and for example different chinaroot greenbrier Saponin/TSM ketone is described with its reduction according to a first aspect of the present invention then.
The heterogeneous catalytic hydrogenation process can suitably use hydrogen and palladium catalyst to carry out in organic solvent.The palladium catalyst preferred negative is loaded on the carriers such as barium sulfate, lime carbonate, graphite or carbon.Preferred palladium is the prereduction attitude.
With dioscin ketone is starting raw material, reduces different chinaroot greenbrier Saponin/TSM ketone with the organo-borane reductive agent that is obstructed behind the shortening, and the product that obtains is different chinaroot greenbrier sapogenin.
With dioscin ketone is starting raw material, reduces different chinaroot greenbrier Saponin/TSM ketone with the organoaluminum hydride reducer behind the shortening, and the product that obtains is the different chinaroot greenbrier sapogenin of table.
The present invention provides the method that 3 Alpha-hydroxies-5 β-H steroid sapogenin and derivative thereof is converted into 3 beta-hydroxies-5 β-H steroid sapogenin and derivative thereof in second aspect, this method comprises, be attended by under the condition of nucleophilic substitution reaction of counter-rotating in the 3-position being suitable for, the 3-hydroxyl activated derivatives of 3 Alpha-hydroxies-5 β-H steroid sapogenin is contacted with nucleophilic reagent, can optionally adjust required 3-substituting group as required subsequently.
S is pressed in this reaction
N2 reaction mechanisms are carried out, and generate required counter-rotating product.A reaction method can mentioning especially is three letter (Mitsonobu) reactions (Hughes, Organic Reactions, 42,337-400 (1992)).When such reaction method was applied on the sapogenin, 3-hydroxyl sapogenin became corresponding 3-ester via its 3-hydroxyl activated state, and 3 are upward reversed simultaneously.Used reagent is dialkyl group azodicarboxylate, triaryl phosphine and appropriate organic or its salt corresponding with the desired ester that obtains.Term " alkyl " preferably contains the alkyl of 1～7 carbon atom.Term " aryl " preferably contains the aryl of 6～12 carbon atoms, and such aryl optionally has alkyl as substituting group.
Another alternative reaction method can comprise the initial preparation of the activated derivatives of the sapogenin that can participate in nucleophilic substitution reaction, as the organic sulfonated derivative of sulfonated on the 3-O position, and for example 3-mesylate derivatives or 3-toluenesulphonic acids ester derivative.
According to a second aspect of the invention, when employed organic acid in the above-mentioned reaction for example contains amino groups, participate in reaction, the protection that available traditional mode is in addition suitable to this group as not wishing it.
In sum, the invention provides from the raw material that is easy to obtain such as diosgenin and synthesize useful steroid sapogenin such as different chinaroot greenbrier sapogenin or show a kind of method of different chinaroot greenbrier sapogenin, this method is used selective reduction to react and is controlled stereochemistry, and this method is represented by these the specific compounds in the following synoptic diagram 1:
Method of the present invention can be used for preparing 3-hydroxyl 5 β-H steroid sapogenin, as chinaroot greenbrier sapogenin, different chinaroot greenbrier sapogenin, table chinaroot greenbrier sapogenin with show different chinaroot greenbrier sapogenin and their derivative.Acceptable form can obtain from described 3-oxy-compound with traditional mode on the prodrug of sapogenin and other physiology, and this content has a detailed description below.
Embodiment
The sapogenin final product
Method of the present invention is preferred for preparing the sapogenin final product that is selected from by the compound of following general formula:
Wherein, R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8And R
9Be mutually independent, and be H, C
1-4Alkyl, OH or OR (R=C herein
6-12Aryl or C
1-4Alkyl); Or R
5And R
6Can represent=O (carbonyl) or protected carbonyl together,
3 of carbon center (that is, on the A ring and radicals R
10The carbon that links to each other) stereochemistry both can be the R configuration and also can be the S configuration, and
R
10Can be glycosyl group or any organic ester group (comprising fatty acid ester and amino acid ester) that hydroxyl, O-connect.
Except the position of indicating with wedge shape line and dotted line conventional representation in the above-mentioned general formula, reaching stereospecificity is outside the feature of the present invention, and the stereochemistry in this general formula is non-specificity, and it has comprised all steric isomers and isomer mixture.
Here " acceptable prodrugs on a physiology " speech of Shi Yonging refers to the prodrug that meets following condition of those the useful compounds among the present invention, and under possible situation the zwitterionic form of the compound among the present invention: in medical science diagnosis and treatment scope reliably, can be used for contacting use, and do not have inappropriate toxicity, pungency, anaphylaxis etc. with human body and zootic tissue; These prodrugs are complementary with rational income/risk ratio, and are effective for its desired use.Term " prodrug " is meant the compound that can transform the parent compound that generation represented by above-mentioned general formula in vivo rapidly, as parent compound as described in producing by the hydrolytic action in the blood.Provide talking out of prodrug in the following document: Design of Prodrugs, H.Bundgaard, Ed., Elsevier, 1985; Methods in Enzymology, people such as K.Widder, Ed., Academic Press, 42, p.309-396,1985; A Textbook of Drug Design and Development, Krogsgaard-Larsen and H.Bundgaard, Ed., Chapter 5; Design and Applicationsof Prodrugs, p.113-193,1991; Advanced Drug Delivery Reviews, H.Bundgaard, 8, p.1-38 (1992); Journal of Pharmaceutical Sciences, 77, p.285 (1988); Chem.Pharm.Bull., people such as N.Nakeya, 32, p.692 (1984); Pro-drugs asNovel Delivery Systems, T.Higuchi and V.Stella, Vol.14 of the A.C.S.Symposium Series, and Bioreversible Carriers in Drug Design, Edward B.Roche, Ed., American Pharmaceutical Association and Pergamon Press, 1978, above document is all introduced the present invention with the form of reference.
" acceptable salt on the physiology " is meant avirulent relatively inorganic acid addition salt, organic acid addition salt and the base addition salt by the compound formation among the present invention.These salt can be in the final separation of compound and purge process on the spot preparation or react with purified compound separately obtain.For example referring to people such as S.M.Berge, Pharmaceutical Salts, J.Pharm.Sci., 66:p.1-19 (1977), this document is introduced the present invention with the form of reference.
Terminology used here " organic ester " is meant by R
10Be this compound of hydroxyl and the organic acid that can become ester react formed any ester or its activated derivatives.In fact, this organic acid can be aliphatic carboxylic acid or amino acid for example.This organic ester group can be selected from without limitation: cathylate (oxyethyl group carbonyl oxygen base) for example, acetic ester, succinate, propionic ester, the butanic acid ester, isobutyrate, valerate, isopentanoate, n-hexoate, dissident's acid esters, the diethyl acetate ester, octanoate, decylate, laurate, myristinate, cetylate, stearate, benzoic ether, phenylacetate, the phenylpropionic acid ester, laurate, phthalyl, glycinate, alanine ester, L-valine ester, the phenylalanine ester, the Isoleucine ester, the methionine(Met) ester, arginine ester, aspartate, cysteine ester, glutamate, the Histidine ester, the Methionin ester, proline ester, serine ester, the Threonine ester, the tryptophane ester, tyrosine ester, fumarate, maleic acid ester; Have substituent aliphatics, as: monochloroacetic acid ester, Methoxy acetic acid ester; Shielded amino acid ester group, as: the amino glycinate (Boc=tertbutyloxycarbonyl) of Boc-, the amino L-valine ester of Boc-, the amino glycinate (CBZ=benzyloxycarbonyl) of CBZ-, the amino L-valine ester of CBZ-; And have substituent aromatic ester groups, as, to bromobenzene methanoyl, a bromobenzene methanoyl, to methoxybenzoyl oxygen base; The chlorinated benzene manthanoate, as, to the chlorinated benzene methanoyl; The dichlorobenzoic acid ester is as the 2,4 dichloro benzene methanoyl; The nitrobenzoyl acid esters, as, p-nitrophenyl methanoyl or 3,5-dinitrobenzene methanoyl etc.
Terminology used here " sugar " refers in particular to monose, disaccharides or trisaccharide and their acylate form.Will not limit such sugar, for example, it can be single aldose or the ketose with 5 or 6 carbon atoms, preferably exists with cyclisation furanose or pyranose form, can be α anomer or β anomer, and has D type or L type optical isomerism.The example of preferred sugar has: glucose; seminose; fructose; semi-lactosi; maltose; cellobiose; sucrose; rhamnosyl; wood sugar; Arabic candy; Fucose; isorhodeose; apiose; lactose; semi-lactosi-glucose; glucose-Arabic candy; Fucose-glucose; rhamnosyl-glucose; glucose-glucose-glucose; glucose-rhamnosyl; seminose-glucose; glucose-(rhamnosyl)-glucose; glucose-(rhamnosyl)-rhamnosyl; glucose-(glucose)-glucose; semi-lactosi-(rhamnosyl)-semi-lactosi and their acidylate (as acetylize) derivative.
The first aspect of invention
In the reactions steps of the required sapogenin of the preparation of first aspect present invention, starting raw material as this step, 3-ketone, in the molecule of 5 β-H steroid sapogenin preferred except that the group of 3-position all sites all consistent with all sites of required sapogenin.But if necessary or desired, can use suitable blocking group, remove these blocking groups then to obtain required sapogenin in order to reduce.
Terminology used here " blocking group " is meant the group that is used for protecting as hydroxyl or carboxyl isoreactivity functional group, when they are the desired group that has of final product, just need avoid them unnecessarily to participate in reaction.Can use traditional blocking group by standard operation, the visible T.W.Green and of specific examples P.G.M.Wuts is in " Protective Groups in Organic Chemistry " JohnWiley and Sons, 1991; J.F.W McOmie in " Protective Groups in OrganicChemistry " Plenum Press, 1973.
Have been found that a large amount of reagent is influential to the selectivity of reaction, also can generation show different chinaroot greenbrier sapogenin thereby both can generate different chinaroot greenbrier sapogenin, as following table 1 listed (selectivity per-cent refers to the per-cent of ingredients constitute crude product).We are surprised to find, use K-Selectride , L-Selectride or N-Selectride (three sec-butyl POTASSIUM BOROHYDRIDE, 3-sec-butyl lithium borohydride or three sec-butyl sodium borohydrides) or corresponding triphenyl-boron hydride, can make 3 beta-hydroxy sapogenins) (as different chinaroot greenbrier sapogenin) form with the three-dimensional selection mode of height.And use the low lithium triethylborohydride reductive agent that is obstructed, 3 Alpha-hydroxy sapogenins (as showing different chinaroot greenbrier sapogenin) are formed with the three-dimensional selection mode of height.We also are surprised to find equally, use organoaluminum hydride such as LTBA that 3 Alpha-hydroxy sapogenins (as showing different chinaroot greenbrier sapogenin) are formed with the three-dimensional selection mode of height.
According to the present invention, at 3-ketone, in the reaction of the Stereoselective reduction of 5 β-H steroid sapogenin, we find, in the final product that obtains, the mol ratio that can obtain primary product 3-hydroxy steroids and another 3-epimer is at least about 10: 1, for example is at least about 15: 1.
The selectivity of table 1 in the reduction reaction of different chinaroot greenbrier Saponin/TSM ketone
| Reagent | Temperature/℃ | Solvent | Different chinaroot greenbrier sapogenin/% | Show different chinaroot greenbrier sapogenin/% | Chinaroot greenbrier ketone/% |
| LiAlH(O tBu) 3 | Room temperature | Tetrahydrofuran (THF) | 5.0 | 95.0 | - |
| LiBHEt 3 | -78 | Tetrahydrofuran (THF) | 22.8 | 74.3 | - |
| *AlH 3 | 0 | Tetrahydrofuran (THF) | 14.4 | 83.1 | - |
| *BH 3 | 0 | Tetrahydrofuran (THF) | 11.8 | 83.9 | - |
| *9-BBN | -78 | Tetrahydrofuran (THF) | 10.4 | 51.4 | 37.5 |
| *NaBH 4/CeCl 3 | -78 | Tetrahydrofuran (THF) | 4.4 | 89.5 | - |
| L-selectride | -78 | Tetrahydrofuran (THF) | 91.1 | 3.4 | 4.7 |
| L-selectride | -5 | Tetrahydrofuran (THF) | 92.7 | 4.2 | 2.5 |
| L-selectride | 20 | Tetrahydrofuran (THF) | 92.7 | 4.8 | 2.2 |
| L-selectride | -78 | Toluene | 90.8 | 5.5 | 2.5 |
| L-selectride | -78 | Diethyl maleate (DEM) | 54.0 | 4.0 | 41.1 |
| L-selectride | 20 | Hexanaphthene | 74.9 | 13.9 | 8.5 |
| N-selectride | -78 | Tetrahydrofuran (THF) | 97.3 | 1.6 | 0.2 |
| N-selectride | -5 | Tetrahydrofuran (THF) | 94.2. | 2.6 | 0.5 |
| K-selectride | -78 | Tetrahydrofuran (THF) | 96.5 | 2.0 | 0.3 |
| K-selectride | -10 | Tetrahydrofuran (THF) | 93.6 | 4.0 | 0.6 |
| K-selectride | -78 | The 2-methyltetrahydrofuran | 92.2 | 6.3 | - |
| LS-selectride | -78 | Tetrahydrofuran (THF) | 91.5 | 4.4 | 3.2 |
| KS-selectride | -78 | Tetrahydrofuran (THF) | 95.5 | 2.4 | 0.3 |
| KBH(Ph) 3 | -78 | Tetrahydrofuran (THF) | 91.0 | 4.6 | 1.7 |
*=contrast reaction;
tBu: the tertiary butyl; Et: ethyl; Ph: phenyl
We are surprised to find, and low temperature (as about-78 ℃) is not the inventive method essential condition.This reduction reaction can be carried out between-100 ℃～25 ℃ usually, and preferable reaction temperature is-40 ℃～25 ℃, and most preferred temperature of reaction is-10 ℃～10 ℃ approximately; Preferred solvent is tetrahydrofuran (THF) (THF), 2-methyltetrahydrofuran (MTHF), toluene, 1, and the mixture of 4-dioxane, t-butyl methyl ether and these solvents, most preferred solvent are tetrahydrofuran (THF) (THF).
In preferred embodiments, starting raw material 3-ketone, 5 β-H steroid sapogenin (as different chinaroot greenbrier Saponin/TSM ketone) can be by corresponding Δ
4, 3-ketone steroid sapogenin (as dioscin ketone) obtains by the heterogeneous catalytic hydrogenation prepared in reaction.
This Δ
4, 3-ketone steroid sapogenin (as dioscin ketone) itself preferably uses corresponding Δ
5, 3-hydroxyl steroid sapogenin (as diosgenin) makes through oxidation, thereby generates the α beta unsaturated ketone.Should be noted in the discussion above that and carry palladium with carbon directly to reduce the primary product that diosgenin obtains as catalyzer be 5 α-product, i.e. tigogenin.
(62,2525 (1940) have confirmed Marker, adopt palladium-barium sulfate catalyzer dioscin ketone can be reduced to different chinaroot greenbrier Saponin/TSM ketone in ethereal solution under atmosphere of hydrogen for people such as Marker, J.Am.Chem.Soc..Lower concentration (500 volumes; The normal processing volume is in 5～30 volume ranges) and high catalyst loading capacity (1000%; Normal catalyzer loading capacity scope is 1%～20%) make described process both infeasible also uneconomical when scale operation.In addition, consider that from safety factors ether is not suitable for scale operation.
Other staff also once studied the reaction that dioscin ketone is reduced into different chinaroot greenbrier Saponin/TSM ketone.Djerassi under normal pressure in ethanol (450ml), on the 10%Pd-C of prereduction (0.8g), reduced dioscin ketone.Thick different chinaroot greenbrier Saponin/TSM ketone can separate by the following method: use water precipitation, again with the chloroform/methanol recrystallization to obtain pure different chinaroot greenbrier Saponin/TSM ketone (7.2g, 72%), its fusing point is 179 ℃～183 ℃.Can not influence the output of reaction when under the condition that has potassium hydroxide (3g), reacting.The fusing point of analytical pure sample is 186 ℃～188 ℃ (Djerassi, Yashin and Rosenkranz, J.Am.Chem.Soc., 74,422 (1952)).Because the solubleness of dioscin ketone in ethanol is lower, there is the shortcoming of concentration low (low dilution) in this method.
In pregnane series, Suvorov found once that pyridine had remarkably influenced to the output of hydrogenation reaction.Be typically in this research work, the catalyzer of selecting for use is 10% the palladium (Pd-CaCO on the lime carbonate of loading on
3).In this case, even add etching reagent, its selectivity also is significantly higher than the reaction (Suvorov and Yaroslavtseva, Steroids, 1270 (1961)) in alcoholic solvent.Used operation also comprises with dilute hydrochloric acid solution cancellation (quench) in the research, and product is extracted in the chloroform.Organic extract is cleaned until reindeer moss is shown neutral with dilute hydrochloric acid, 8% sodium bicarbonate aqueous solution and water.These class methods produce the water-based waste that includes pyridine and halogenated solvent that needs processing in a large number, thereby have increased processing cost.
Irismetov once confirmed, can obtain highly selective in the process that dioscin ketone is reduced to different chinaroot greenbrier Saponin/TSM ketone.In this research, the hydrogenation of dioscin ketone (1g) is under normal pressure, with 5%Pd-CaCO
3(1g) be catalyzer, in pyridine (30ml), carry out.After removing by filter catalyzer and evaporating solvent, resistates recrystallization from alcohols is come out, obtain fusing point and be 209 ℃～211 ℃ solid.Output do not appear in the newspapers (Irismetov and Goryayev, Izv.Akad.Nauk Kaz.SSR, Ser.Khim., 2,47 (1982)).For scale operation, the deficiency of this research is high catalyst loading capacity (100%) and dilute solution.Pyridine is a noxious solvent, and it more commonly is used as the scavenging agent of acid by stoichiometry in scale operation.
The claimed following method of reducing of No. the 736th, 818, United States Patent (USP): adopt palladium catalyst, in mineral alkali and anhydrous medium with 3-ketone-Δ
4-steroide is reduced to 5 β-H steroide.Preferred solvent is a methyl alcohol, and preferred alkali is potassium hydroxide.The example of relevant dioscin ketone is not provided.We find that dioscin ketone solubleness in alcohols (especially ethanol) is very low, and this will cause the reaction density of this method rare excessively.This method also needs extraction process.
United States Patent (USP) is mentioned for the 736th, No. 301, at reduction 3-ketone-Δ
4In-steroide the process, utilize alkali (being sodium hydroxide or potassium hydroxide) to increase the amount of 5 β-H product.This patent specific requirement protection triethylamine application in this case.In the solvent of selecting for use, enumerated ethanol, ether, vinyl acetic monomer and methylcyclohexane, preferred solvent is 1, the 4-dioxane.
We find pleasantly surprisedly, the palladium (as: Pd-BaSO of working load on carrier (as barium sulfate or lime carbonate) in The suitable solvent
4Or Pd-CaCO
3) can obtain a kind of both economical and scalable method as catalyzer.Specifically, we have found and can carry out method of operating with economically viable concentration when using the low catalyst loading capacity.And the ortho states of going back that we are surprised to find these catalyzer has more selectivity than their ortho states of not going back, and is as shown in table 2.
Table 2: conventional screening study
| Catalyst/solvent | Different chinaroot greenbrier Saponin/TSM ketone/% | Smart ketone/the % of cautious announcement | Dioscin ketone/% | Tigogenin/% |
| Pd-BaSO 4(r)/THF | 95.7 | 2.1 | ＜0.1 | 1.2 |
| Pd-BaSO 4(u)/THF | 84.0 | 13.1 | - | - |
| Pd-CaCO 3(r)/THF | 91.4 | 6.9 | - | 1.7 |
| Pd-CaCO 3(u)/THF | 81.1 | 14.2 | - | 1.7 |
Annotate: (r) represent the ortho states of going back of catalyzer, (u) represent the ortho states of not going back of catalyzer.
5%Pd/ graphite (Johnson Matthey 450 types) and 10%Pd/C (Johnson Matthey 39 types) also are the catalyzer that is suitable in this method.
Preferred solvent can be selected from tetrahydrofuran (THF) (THF), 2-methyltetrahydrofuran, toluene, 1,4-dioxane, vinyl acetic monomer, methyl iso-butyl ketone (MIBK); Most preferred solvent is THF.Find that these solvents all are better than pyridine.With these materials is solvent, and the operation concentration of this method can be 1～50 volume, is preferably 3～30 volumes, most preferably is 3～10 volumes.The catalyzer loading capacity is preferably 1%～10% in 1%～25% scope, most preferably be 1%～5%.
We are surprised to find, and increase pressure and can cause the selectivity of this method to descend.This reaction is preferably carried out under the hydrogen pressure of 1～5 crust, most preferably is 1～2 crust hydrogen pressure.
The rising of also finding temperature can reduce selectivity equally.Temperature of reaction is preferably 15 ℃～75 ℃, more preferably 20 ℃～50 ℃, most preferably is 20 ℃～30 ℃.
Than ethanol and other possible ether replace solvents (as methylene diethyl ether and t-butyl methyl ether), THF can increase the solubleness of dioscin ketone.This provides output higher and more economical method.Compare with ethanol/aqueous sodium hydroxide solution system, this method provides more simple operation.
This operation is made up of with dividing divorce chinaroot greenbrier Saponin/TSM ketone concentrated reaction mixture.Solvent can recycle arbitrarily.
Many solvents can be used to the different chinaroot greenbrier Saponin/TSM of purifying ketone effectively, comprising: hexanaphthene, 2-butanone, acetone, 2-propyl alcohol and methyl alcohol; Example is seen shown in the following table 3:
The recrystallization of the thick different chinaroot greenbrier Saponin/TSM ketone of table 3
| Solvent | Volume | Productive rate/% | Different chinaroot greenbrier Saponin/TSM ketone/% | Smart ketone/the % of cautious announcement | Dioscin ketone/% | Tigogenin/% |
| Input amount | - | - | 91.35 | 5.15 | 1.71 | 1.27 |
| 2-butanone | 5 | 70 | 97.77 | 1.20 | 0.39 | 0.5 1 |
| Hexanaphthene | 8 | 72 | 97.71 | 1.10 | 0.33 | 0.57 |
| The 2-propyl alcohol | 12 | 60 | 97.40 | 1.35 | 0.37 | 0.71 |
A preferred aspect of the present invention is the THF solution of different chinaroot greenbrier Saponin/TSM ketone to be directly used in the described reduction reaction of first aspect present invention after hydrogenation.This has been avoided the separation and the drying process of the different chinaroot greenbrier Saponin/TSM of intermediate ketone, has saved the time and has reduced the use of equipment, therefore is expected to reduce production costs.We are surprised to find, and the impurity that this method produces (mainly being table tigogenin and different chinaroot greenbrier sapogenin) can be removed by the thick different chinaroot greenbrier sapogenin of recrystallization.
The second aspect of invention
The present invention provides the method that 3 Alpha-hydroxies-5 β-H steroid sapogenin and derivative thereof is converted into 3 beta-hydroxies-5 β-H steroid sapogenin and derivative (as the ester class) thereof by stereotaxis counter-rotating reaction in second aspect.For example, by di-isopropyl azodicarboxylate, triphenylphosphine and benzoic effect is so-called three letter reaction (Hughes, Organic Reactions, 42,337-400 (1992)), can successfully table chinaroot greenbrier sapogenin be converted into new compound chinaroot greenbrier sapogenin benzoic ether.Therefore, chinaroot greenbrier sapogenin benzoic ether and preparation method thereof has constituted further feature of the present invention.With similar mode, the different chinaroot greenbrier sapogenin of table can be converted into known ester is different chinaroot greenbrier sapogenin benzoic ether.Present method is not limited to prepare benzoic ether, also can be effectively used to prepare fatty acid ester, as: acetic ester, propionic ester, butanic acid ester, isobutyrate, n-hexoate, dissident's acid esters, cetylate; Have substituent fatty acid ester, as: monochloroacetic acid ester, Methoxy acetic acid ester; Shielded amino ester is as the amino glycinate of Boc-, the amino L-valine ester of Boc-, the amino glycinate of CBZ-, the amino L-valine ester of CBZ-; Or have substituent aromatic ester, as chlorinated benzene manthanoate, nitrobenzoyl acid esters and dichlorobenzene manthanoate etc.
As selection, this reaction method also can comprise generation 3 α earlier, and the activated form of 5 β-sapogenin is as methane sulfonate (methanesulfonates) or p-toluenesulfonic esters (tosylate).Make this activated form and anion of carboxylic acid salt (as sodium salt, cesium salt or sylvite) that nucleophilic substitution reaction takes place subsequently in a conventional manner.
The recovery of gained compound
The prepared compound of either side of the present invention all can reclaim from reaction mixture by traditional method.For example, can from reaction mixture, steam solvent reclaiming this compound, or if necessary, can be after from reaction mixture, steaming solvent, residue is poured in the water, used subsequently and the immiscible organic solvent extraction of water, this solvent is evaporated from extraction liquid remove again.In addition, if necessary, available various well-known technology are further purified product, as adopting recrystallization, redeposition or various chromatographic technique, especially column chromatography or preparative thin layer chromatography.
Embodiment
Following examples have been set forth by adopting the selective reduction reaction with the control stereochemistry, obtain showing chinaroot greenbrier sapogenin, different chinaroot greenbrier sapogenin and show different chinaroot greenbrier sapogenin thereby synthesize, but the present invention is not limited thereto.These embodiment have also set forth from 3 Alpha-hydroxies, and 5 β-H sapogenin is to 3 beta-hydroxies, and 5 β-H sapogenin and derivative thereof are made the method that stereospecificity transforms.
Embodiment 1
Synthesize different chinaroot greenbrier sapogenin with L-Selectride by different chinaroot greenbrier Saponin/TSM ketone at-10 ℃
Different chinaroot greenbrier Saponin/TSM ketone (657g) is dissolved in the tetrahydrofuran (THF) (4000ml), and with this solution of nitrogen purging, and cooling solution is to internal temperature Yue Da-10 ℃.With adding L-Selectride (the THF solution 2400ml of 1 M) in the solution in about 50 minutes and stirring 90 minutes.Slowly add water (2000ml) solution of citric acid (600g), maintain the temperature at below 0 ℃.This mixture is warming up to room temperature and stirred 30 minutes.Separate water layer, and with layering again after methylene dichloride (2000ml) aqueous layer extracted.Water layer extracts with methylene dichloride (1500ml).Use MgSO after organic extract liquid water (4000ml) washing that merges
4Dry.The evaporate to dryness organic extract liquid promptly gets different chinaroot greenbrier sapogenin.
Embodiment 2
Synthesize different chinaroot greenbrier sapogenin with K-Selectride by different chinaroot greenbrier Saponin/TSM ketone at-15 ℃
Approximately under-15 ℃ the condition, in tetrahydrofuran (THF) (3500ml) solution of different chinaroot greenbrier Saponin/TSM ketone (500g), add K-Selectride (1600ml, the THF solution of 1M) at nitrogen atmosphere, temperature.Under this temperature, reaction mixture was stirred 30 minutes.With aqueous citric acid solution (the 393g citric acid is dissolved in the 1300ml water) cancellation, keep internal temperature to be about 0 ℃.This mixture is warmed up to room temperature, and under normal pressure, allows the THF evaporation until solid precipitation.Crossing filter solid and pump does.
With solid be dissolved in methylene dichloride (DCM) (6000ml) in, dry (use MgSO
4) and evaporation obtain a white solid, Virahol (IPA) (5000ml) in recrystallization, obtain different chinaroot greenbrier sapogenin.
Embodiment 3
Synthesize different chinaroot greenbrier sapogenin with N-Selectride by different chinaroot greenbrier Saponin/TSM ketone at-78 ℃
-78 ℃ with 10 minutes the different chinaroot greenbrier Saponin/TSM of clockwise ketone (206mg) tetrahydrofuran (THF) (10ml) solution in add N-Selectride (0.64ml, the THF solution of 1M).Stir the mixture, and with 10% aqueous citric acid solution (the 2g citric acid is dissolved in the 20ml water) cancellation, product (after 2 * 50ml) extractions, dryly (is used MgSO with DCM
4) and evaporation obtain a colorless oil.(20ml) absorbs this oily matter with acetone, adds entry (50ml) then.Filter collecting precipitation, drying obtains different chinaroot greenbrier sapogenin (200mg, 97%).
Embodiment 4
By the synthetic different chinaroot greenbrier Saponin/TSM ketone of dioscin ketone
40 ℃～45 ℃ dioscin ketone (500g) is dissolved in tetrahydrofuran (THF) (THF) (2500ml) in, and with this solution of nitrogen inerting.Add 5%Pd-BaSO
4(going back ortho states) (100g); With this flask of hydrogen purge, stir about is 6.5 hours under hydrogen atmosphere.The cooling flask removes by filter catalyzer to room temperature by Celite (diatomite) pad (50g).Evaporating solvent obtains solid residue, promptly thick different chinaroot greenbrier Saponin/TSM ketone.
Repeat said process,, and at room temperature, in nitrogen atmosphere, mixed slurry about 30 minutes again with hexanaphthene (2260ml) with the product merging (902.8g) of two batches of gained.By filter and in about 40 ℃ vacuum oven dried overnight, obtain pure different chinaroot greenbrier Saponin/TSM ketone (749.1g, 75%).
Embodiment 5
By the synthetic different chinaroot greenbrier Saponin/TSM ketone of dioscin ketone
With dioscin ketone (700g) be dissolved in tetrahydrofuran (THF) (THF) (4500ml) in, and with this solution of nitrogen inerting.After handling this mixture with activated carbon (35g), under 25 ℃ and 2.5 crust hydrogen conditions, at 5%Pd-BaSO
4(going back ortho states) (35g) go up to take place that hydrogenation sends out should.Remove by filter catalyzer, and mixture is concentrated to about 1/4th volumes.In about 30 minutes time, add entry (3000ml), leach the solid of gained.With methyl alcohol (560ml) washing solid,, promptly get different chinaroot greenbrier Saponin/TSM ketone (630g, 90%) 40 ℃～50 ℃ vacuum-dryings
Embodiment 6
The socket of hydrogenation reaction and reduction reaction
With dioscin ketone (500g) be dissolved in tetrahydrofuran (THF) (THF) (2500ml) in, and with this solution of nitrogen inerting.Add Pd-BaSO
4(going back ortho states) (100g); With this flask of hydrogen purge, stir about is 5 hours under hydrogen atmosphere.(20g) removes by filter catalyzer by the Celite pad.Resistates is directly used in next step with tetrahydrofuran (THF) (1000ml) washing with this solution.
At nitrogen atmosphere, temperature approximately under-15 ℃ the condition, in tetrahydrofuran solution, add K-Selectride (1600ml, the tetrahydrofuran solution of 1M) from the different chinaroot greenbrier Saponin/TSM ketone (500g) of above step.Under this temperature, reaction mixture was stirred 30 minutes,, keep internal temperature to be about 0 ℃ with aqueous citric acid solution (the 393g citric acid is dissolved in the 1300ml water) cancellation.This mixture is warming up to room temperature, and the evaporation tetrahydrofuran (THF) is until solid precipitation is arranged under normal pressure.Leaching this solid and pump does.
This solid is dissolved in the methylene dichloride (6000ml), and drying (is used MgSO
4) and evaporation obtain a white solid, with 2-propyl alcohol (5000ml) recrystallization.With acetone (5000ml) to the further recrystallization of solid.With acetone (3500ml) to the further recrystallization of solid.The solid that obtains is dry in 80 ℃ vacuum oven, promptly get pure different chinaroot greenbrier sapogenin (154.5g).
Fusing point: 184.7～187.0 ℃; [α]
D 20=-73.3 °; IRv
Max3456,2928,1451,1376,1050,979,896cm
-1ESI-MS m/z 417[M+1]
+ 1H NMR (CDCl
3, 300MHz): particularly, δ 4.39 (1H, br q, J=8Hz), 4.10 (1H, br s), 3.46 (1H, br dd, J=11Hz), 3.39 (1H, t, J=11Hz), 0.98 (3H, s), 0.97 (3H, d, J=7Hz), 0.79 (3H, d, J=7Hz), 0.76 (3H, s) ppm;
13C NMR (CDCl
3, 126MHz): δ 14.47,16.43, and 17.10,20.83,23.86,26.48,26.50,27.75,28.73,29.89,30.24,31.32,31.73,33.46,35.21,35.21,36.45,39.78,40.24,40.63,41.54,56.41,62.19,66.79,66.98,80.87,109.20ppm; C 77.94%; H10.75% (C
27H
44O
3Theoretical value: C 77.84%; H10.64%).
Embodiment 7
The socket of hydrogenation reaction and reduction reaction
Under-10 ℃ of pacts, nitrogen atmosphere, in the tetrahydrofuran solution (hydrogenation reaction by dioscin ketone obtains) of different chinaroot greenbrier Saponin/TSM ketone (156g), add L-Selectride (527ml, the tetrahydrofuran solution of 1M).Under this temperature, reaction mixture was stirred 30 minutes, be warming up to again to stir after the room temperature and spend the night.Carry out cancellation by the mixture that in this mixture, adds aqueous citric acid solution (311g is dissolved in the 3800ml water) and methylene dichloride (2200ml), keep internal temperature to be lower than 30 ℃.After the aqueous phase separation, extract again with methylene dichloride (400ml).The organic extract liquid that merges is washed with aqueous citric acid solution (160g is dissolved in the 2200ml water), be distilled to less volume.Add 2-propyl alcohol (3000ml), with the mixture redistillation to about 1/2 volume.Add other 2-propyl alcohol (1500ml) again, with mixture distillation to about 1/2 volume.The reflux mixture makes it cooling again.Further cooling mixture to 0～l0 ℃, and filter.Drying solid in 60 ℃～65 ℃ vacuum oven obtains different chinaroot greenbrier sapogenin.Output is 94.0g.
Embodiment 8
Different chinaroot greenbrier Saponin/TSM ketone is reduced to the different chinaroot greenbrier sapogenin of table
(32.0g, (tetrahydrofuran solution of 1M, 99ml), its drop rate is deserved to keep 14 ℃～16 ℃ temperature to drip three tert.-butoxy aluminium lithium hydrides in tetrahydrofuran (THF) 77.2mmol) (800ml) solution to different chinaroot greenbrier Saponin/TSM ketone.After being added dropwise to complete, at room temperature continued immediately to stir the mixture 2 hours.The careful ammonium chloride solution (30g ammonium chloride is dissolved in the 400ml water) that adds is with the remaining reductive agent of cancellation.Filtering mixt is with methylene dichloride (300ml) washing solid.The filtrate that evaporation merges is distinguished residue between methylene dichloride (300ml) and water (300ml).(2 * 300ml) further extract water layer with methylene dichloride.With the organism drying (MgSO that merges
4), evaporation obtains a white solid (25.7g).With this solid acetone (1250ml) recrystallization, with solid (19.0g) dried overnight in 40 ℃ vacuum oven that obtains.Be further purified this solid by heating this solid acetone (1425ml) suspension.The solid that obtains is dried overnight in 40 ℃ vacuum oven.At last, in 2-propyl alcohol (300ml), solid is carried out recrystallization to be purified, filter any inorganics by solution heat then.After the filtrate cooling, leach solid, and, promptly get and show different chinaroot greenbrier sapogenin (9.0g) this solid dried overnight in 60 ℃ vacuum oven.
Fusing point: 223～227 ℃; [α]
D 25=-64 ° of (c=5g L
-1, CHCl
3); IRv
Max(KBr) 3392,2937,1451,1369,1051,982,864cm
-1ESI-MS m/z 417[M+1]
+ 1H NMR (CDCl
3, 300 MHz): particularly, δ 4.40 (1H, br q, J=8Hz), 3.62 (1H, septet, J=10,10,5,5 Hz), 3.48 (1H, br dd, J=11Hz), 3.37 (1H, t, J=11Hz), 0.97 (3H, d, J=7Hz), 0.95 (3H, s), 0.79 (3H, d, J=7Hz), 0.75 (3H, s) ppm;
13C NMR (CDCl
3, 75MHz) particularly: δ 14.91,16.85, and 17.55,20.99,23.78,27.08,27.49,30.68,31.75,32.18,35.09,35.75,35.85,40.62,40.91,41.04,41.99,42.39,56.74,62.59,67.23,72.10,81.30,109.64ppm; C 77.77%; H 10.59% (C
27H
44O
3Theoretical value: C 77.84%; H 10.64%).
Embodiment 9
By the synthetic different chinaroot greenbrier sapogenin benzoic ether of the different chinaroot greenbrier sapogenin of table
With di-isopropyl azodicarboxylate (0.81g, 4.0mmol) dried THF (2ml) solution join the different chinaroot greenbrier sapogenin of table (0.83g through stirring, 2.0mmol), (1.05g, 4.0mmoL) (0.49g is in dried THF (20ml) solution 4.0mmol) with phenylformic acid for triphenylphosphine.At room temperature stir the mixture, (TLC) monitored with tlc.After 2 hours, all starting raw materials all are consumed.Vacuum is dissolved in residual soup compound in the ether (30ml) after removing solvent, and (25ml) washs this solution with saturated sodium bicarbonate aqueous solution.Organic layer MgSO
4Drying, and by the thin silicon pad, with ether washing silicon pad.With washings and the filtrate vacuum concentration that merges, promptly get the different chinaroot greenbrier sapogenin benzoic ether of white solid.
Embodiment 10
By the synthetic chinaroot greenbrier sapogenin benzoic ether of table chinaroot greenbrier sapogenin
With di-isopropyl azodicarboxylate (0.81g, 4.0mmol) dried THF (2ml) solution join table chinaroot greenbrier sapogenin (0.83g through stirring, 2.0mmol), (1.05g, 4.0mmol) (0.49g is in dried THF (20ml) solution 4.0mmol) with phenylformic acid for triphenylphosphine.At room temperature stir the mixture, (TLC) monitored with tlc.After 2 hours, all starting raw materials all are consumed.Vacuum is dissolved in residual soup compound in the ether (30ml) after removing solvent, and (25ml) washs this solution with saturated sodium bicarbonate aqueous solution.Organic layer MgSO
4Drying, and by the thin silicon pad, with ether washing silicon pad.With washings and the filtrate vacuum concentration that merges, promptly get the chinaroot greenbrier sapogenin benzoic ether of white solid.
Fusing point: 173～175 ℃;
1HNMR (500MHz, CDCl
3): δ 0.77 (3H, s, 18-CH
3), 1.00 (3H, d, J=6.7Hz, 21-CH
3), 1.04 (3H, s, 19-CH
3), 1.08 (3H, d, J=7.0Hz, 27-CH
3), 1.1-2.1 (27H, complicated multiplet, aliphatics), 3.31 (1H, br.d, J=10.9Hz, 26-OCHH), 3.96 (1H, br.dd, J=10.9,2.0Hz, 26-OCHH), 4.42 (1H, m, 16-OCH), 5.34 (1H, br.s, H-3), 7.44 (2H, br.t, J=7.6Hz, aromatic hydrocarbon H), 7.55 (1H, br.t, J=7.6Hz, aromatic hydrocarbon H), 8.05 (1H, br.d, J=7.6Hz, aromatic hydrocarbon H) ppm;
13C NMR (125.6MHz, CDCl
3): δ 14.56,16.28, and 16.71,21.17,24.28,25.41,26.01,26.19,26.69,27.31,31.02,31.33,31.98,35.37,35.57,37.92,40.28,40.48,40.91,42.36,56.63 (C-14), 62.33 (C-17), 65.36 (C-26), 71.54 (C-3), 81.22 (C-16), 109.94 (C-22), (128.54 aromatic hydrocarbon C), 129.73 (aromatic hydrocarbon C), 131.39 (aromatic hydrocarbon C), 132.9 (aromatic hydrocarbon C), 166.13 (carbonyl) ppm.
Embodiment 11
By the synthetic table of chinaroot greenbrier Saponin/TSM ketone chinaroot greenbrier sapogenin
Under-23 ℃～-30 ℃, exsiccant nitrogen atmosphere, (1M 41.71kg) joins in dried THF (about 70kg) stirred solution of chinaroot greenbrier Saponin/TSM ketone (17.38kg) (the interpolation time is about 2 hours) with the tetrahydrofuran solution of three tert.-butoxy aluminium lithium hydrides.With THF washing reaction pipeline, stirred the mixture about 3 hours at-23 ℃～30 ℃.The solution that obtains is used aqueous sodium persulfate solution (5.67kg sodium sulfate is dissolved in the 28.67kg water) cancellation carefully.Filter and remove inorganic salt, and wash with THF (184kg).Add entry (63.18kg), most of THF is removed in distillation.Add water (126.44kg) again, the filtering separation product.Water (2 * 17.38kg) and acetone (4 * 13.73kg) washed product.At 35 ℃～40 ℃ these products of drying, promptly get and show chinaroot greenbrier sapogenin (14.48kg).
More than the present invention has been carried out wide in range non restrictive description.Conspicuous change includes in the scope of the application and later patents with correction concerning those skilled in the art.
Claims (24)
1. method that 3 Alpha-hydroxies-5 β-H steroid sapogenin and derivative thereof is converted into 3 beta-hydroxies-5 β-H steroid sapogenin and derivative thereof, this method comprises: be suitable under the condition of 3 nucleophilic substitution reactions that are attended by counter-rotating, the 3-hydroxyl activated derivatives of 3 Alpha-hydroxies-5 β-H steroid sapogenin is contacted with nucleophilic reagent, and optionally as required described 3 bit substituents are carried out follow-up adjustment.
2. the method for claim 1, wherein described reaction is carried out according to three letter reaction methods, thereby generates the ester derivative of 3 beta-hydroxies-5 β-H steroid sapogenin.
3. the method for claim 1, wherein the activated derivatives of described sapogenin is organic sulfonated derivative.
4. as each described method of above claim, wherein, described 3 Alpha-hydroxies-5 β-H steroid sapogenin is a table chinaroot greenbrier sapogenin.
5. as each described method of above claim, wherein, described 3 Alpha-hydroxies-5 β-H steroid sapogenin is the different chinaroot greenbrier sapogenin of table.
6. as each described method of above claim, wherein, the 3-hydroxyl activated derivatives of described 3 Alpha-hydroxies-5 β-H steroid sapogenin makes by the following method: use reductive agent to reduce 3-ketone-5 β-H steroid sapogenin, subsequently the 3 Alpha-hydroxies-5 β-H steroid sapogenin of gained is converted into the 3-hydroxyl activated derivatives of 3 Alpha-hydroxies-5 β-H steroid sapogenin, described reductive agent comprises containing to have the organo-borane or the organoaluminum hydride of the organic group of two carbon atoms at the most.
7. method as claimed in claim 6, wherein, described organo-borane is a lithium triethylborohydride.
8. method as claimed in claim 6, wherein, described organoaluminum hydride is three tert.-butoxy aluminium lithium hydrides.
9. as each described method in the claim 6～8, wherein, the main sapogenin that is obtained and the mol ratio of another 3-epimer were at least 10: 1.
10. method as claimed in claim 9, wherein, described mol ratio was at least 15: 1.
11. as each described method in the claim 6～10, wherein, described reduction is carried out in being selected from the organic solvent of following material: tetrahydrofuran (THF), toluene, t-butyl methyl ether, methylene diethyl ether, 1,4-dioxane and 2-methyltetrahydrofuran.
12. method as claimed in claim 11, wherein, described organic solvent is made up of tetrahydrofuran (THF).
13. method as claimed in claim 11, wherein, described organic solvent is made up of toluene.
14. method as claimed in claim 11, wherein, described organic solvent is by 1, and the 4-dioxane is formed.
15. method as claimed in claim 11, wherein, described organic solvent is made up of the 2-methyltetrahydrofuran.
16. as each described method in the claim 6～15, wherein, the desired sapogenin that obtains is the compound of being represented by following general formula:
Wherein, R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8And R
9Be independent of each other, and be H, C
1-4Alkyl, OH or OR, R=C herein
6-12Aryl or C
1-4Alkyl; Perhaps, R
5And R
6Expression=O is carbonyl or shielded carbonyl together, and the stereochemistry at 3 places of carbon center is R configuration or S configuration, and R
10Glycosyl group or any organic ester group that representation hydroxy, O-connect.
17. as each described method in the claim 6～16, wherein, 3 Alpha-hydroxies-5 β that make in described reduction-H steroid sapogenin and derivative thereof are selected from table chinaroot greenbrier sapogenin, the different chinaroot greenbrier sapogenin of table and their ester class.
18. as each described method in the claim 1～17, wherein, 3 beta-hydroxies-5 β that make in described conversion-H steroid sapogenin and derivative thereof are selected from chinaroot greenbrier sapogenin, different chinaroot greenbrier sapogenin and their ester class.
19. as each described method in the claim 6～17, wherein, described starting raw material 3-ketone, 5 β-H steroid sapogenin is by corresponding Δ
4, the heterogeneous catalytic hydrogenation prepared in reaction of 3-ketone steroid sapogenin, described heterogeneous catalytic hydrogenation reaction is with described Δ
4, the major part at least in the 3-ketone steroid sapogenin is converted into described 5 β-H, 3-ketone.
20. method as claimed in claim 19, wherein, described heterogeneous catalytic hydrogenation reaction utilizes hydrogen and palladium catalyst to carry out in organic solvent.
21. method as claimed in claim 20, wherein, described palladium catalyst loads on the carrier.
22. as each described method in the claim 14～16, wherein, described Δ
4, 3-ketone steroid sapogenin is a dioscin ketone.
23. method as claimed in claim 22, wherein, described dioscin ketone is to obtain by the oxidation diosgenin.
24. as each described method of above claim, wherein, with formed sapogenin be subsequently converted to they prodrug or other physiology on acceptable form.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0225106.4 | 2002-10-28 | ||
| GB0225106A GB0225106D0 (en) | 2002-10-28 | 2002-10-28 | Synthesis of 3 hydroxy-5 -steroids |
| GB0301505.4 | 2003-01-22 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB038247445A Division CN100486989C (en) | 2002-10-28 | 2003-04-28 | Stereospecific reduction of sapogen-3-ones |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101195650A true CN101195650A (en) | 2008-06-11 |
Family
ID=9946753
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB038247445A Expired - Fee Related CN100486989C (en) | 2002-10-28 | 2003-04-28 | Stereospecific reduction of sapogen-3-ones |
| CNA2007101699386A Pending CN101195650A (en) | 2002-10-28 | 2003-04-28 | Process of stereospecific synthesis of sapogenins |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB038247445A Expired - Fee Related CN100486989C (en) | 2002-10-28 | 2003-04-28 | Stereospecific reduction of sapogen-3-ones |
Country Status (3)
| Country | Link |
|---|---|
| CN (2) | CN100486989C (en) |
| GB (1) | GB0225106D0 (en) |
| UA (1) | UA81133C2 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009132478A1 (en) * | 2008-04-30 | 2009-11-05 | Phytopharm Plc | Synthesis of timosaponin bii |
-
2002
- 2002-10-28 GB GB0225106A patent/GB0225106D0/en not_active Ceased
-
2003
- 2003-04-28 UA UAA200504643A patent/UA81133C2/en unknown
- 2003-04-28 CN CNB038247445A patent/CN100486989C/en not_active Expired - Fee Related
- 2003-04-28 CN CNA2007101699386A patent/CN101195650A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| CN1723218A (en) | 2006-01-18 |
| UA81133C2 (en) | 2007-12-10 |
| GB0225106D0 (en) | 2002-12-11 |
| CN100486989C (en) | 2009-05-13 |
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Open date: 20080611 |