CN101018802A - Method for producing steroid compound - Google Patents

Method for producing steroid compound Download PDF

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CN101018802A
CN101018802A CN 200580030630 CN200580030630A CN101018802A CN 101018802 A CN101018802 A CN 101018802A CN 200580030630 CN200580030630 CN 200580030630 CN 200580030630 A CN200580030630 A CN 200580030630A CN 101018802 A CN101018802 A CN 101018802A
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expression
ketone
acid
formula
steroid
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竹原润
藤原尚哉
河井润也
远藤恭子
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Mitsubishi Chemical Corp
Mitsubishi Kasei Corp
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Mitsubishi Kasei Corp
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Abstract

An object of the present invention is to provide a novel method for producing a steroid compound. The present invention provides a method for producing 3,7-dioxo-5beta-cholanic acid or ester derivatives thereof, which uses, as raw materials, sterols having double bonds at positions 5 and 24, such as cholesta-5,7,24-trien-3beta-ol, ergosta-5,7,24(28)-trien-3beta-ol, desmosterol, fucosterol, or ergosta-5,24(28)-dien-3beta-ol, and which comprises the following 4 steps: (I) a step of performing oxidation of a hydroxyl group at position 3 and isomerization of a double bond at position 5 to position 4; (II) a step of converting position 24 to a carboxyl group or an ester derivative thereof by the oxidative cleavage of a side chain; (III) a step of introducing an oxygen functional group into position 7; and (IV) a step of constructing a 5beta-configuration by reduction of a double bond at position 4.

Description

The preparation method of steroid
Technical field
The present invention relates to the preparation method of steroid, in detail, relate to preparation 3, the method of 7-dioxo-5 β-cholanic acid or its ester derivative, it is to carry out 5 β spatial structure by the steroid reduction saturation that has two keys with 4, say in further detail, relate to a kind of preparation 3, the method for 7-dioxo-5 β-cholanic acid or its ester derivative, the courage steroid-5 of this method to have the sterols of two keys at 5 and 24,7,24-triolefin-3 β-alcohol, or ergot steroid-5,7,24 (28)-triolefins-3 β-alcohol, desmosterol or fucosterol, ergot steroid-5,24 (28)-diene-3 β-alcohol is raw material, and through 4 following steps, that is:
(I) carry out the oxidation of 3 hydroxyls and 5 two keys to 4 isomerized step;
(II) cut off 24 steps that become carboxyl or its ester derivative by the oxidation of side chain;
(III) 7 steps that import oxygen functional group;
(IV) carry out the three-dimensional step that makes up of 5 β by the reduction saturation of 4 two keys.
In further detail, the present invention relates to prepare 3, the method for 7-dioxo-5 β-cholanic acid or its ester derivative, wherein, with courage steroid-5,7,24-triolefin-3 β-alcohol is raw material, adopts chemical synthesis, and through courage steroid-4,6,24-triolefin-3-ketone.This 3,7-dioxo-5 β-cholanic acid or its ester derivative are useful as the synthetic intermediate of pharmaceuticals such as Ursodeoxycholic Acid (UDCA) or gallodesoxycholic acid.
In addition, the present invention relates to courage steroid-4,6, the preparation method of 24-triolefin-3-ketone, this method are with courage steroid-5,7, and 24-triolefin-3-alcohol is raw material.This resultant is useful as the synthetic intermediate of various steroid class pharmaceuticals.
Background technology
As 3, the preparation method of 7-dioxo-5 β-cholanic acid or its ester derivative, reported by (for example from the method for their hydroxyl of raw material oxidation of the same skeleton/same carbonatoms of the gallodesoxycholic acid of bile acide or Ursodeoxycholic Acid (UDCA) etc., open clear 52-78864 communique with reference to the spy, the spy opens clear 52-78863 communique, No. 489661 specification sheets of Spain's patent, No. 2453182 specification sheets of French Patent, Japan's The Chemicals 1955,76 volumes, 297 pages, and J.Chem.Soc., Perkin.1,1990,1 volume, 1 page), in addition, as the preparation method of these gallodesoxycholic acids or Ursodeoxycholic Acid (UDCA), reported (1) mainly with the bile acide that in animal, contains be raw material method (for example, open clear 64-61496 communique with reference to the spy, Te Kaiping 3-5399 communique, Japan's The Chemicals 1955,76 volumes, 297 pages, and J.Chem.Soc., Perkin.1,1990,1 volumes, 1 page); (2) derive from the steroid class deutero-method (for example, with reference to No. 1217336 specification sheets of Chinese patent and Yunnan University's journal, natural science edition, 1998,20 volumes, 399 pages) of plant by Stigmasterol etc.; (3) by few raw material deutero-method of side chain carbon numbers such as progesterone (for example, with reference to No. 1308085 specification sheets of Chinese patent) etc.
, for (1),, be at high price owing to be from natural raw material, be difficult to obtain sufficient quantity, cheap chemical synthesis is established in expectation.In addition, for (2) and (3), same with (1), owing to be, be high price, and need be used to make the carbonatoms of side chain to meet the step of desired compounds and be used to import the multistep oxidation step etc. of 7 functional groups from natural raw material, total number of steps is very many, is uneconomic.
On the other hand, for example, at Org.Synth.Col.Vol.III, disclose in 1955,207 pages 5 are had two keys and carry out the method that Ovshinsky oxidation (OppenauerOxidation) prepares 3-oxo-4-alkene steroid at 3 steroids with hydroxyl.
In addition, as making up 5 β spatial methods, for example, and open WO02/088166 communique and Steroids in the world, 1983,42 volumes, No. 6, in 707 pages, it is effective disclosing 4 two keys reduction saturation.
In addition, as 7 methods that import oxygen functional group at steroid, for example, at Helv.Chim.Acta, 1971,54 volumes, No. 8, disclose in 2775 pages 3-oxo-4,6-diene steroid carries out epoxidation and changes into 3-oxo-4-alkene-6, the method for 7-epoxy steroid compounds, in addition, for example, at Appl.Environ.Microbiol., 1986,51 volumes, in 946 pages, the method for utilizing microorganism 3-oxo-4-alkene steroid to be changed into 3-carbonyl-4-alkene-7-alcohol steroid is disclosed.In addition, for example, at J.Chem.Res., Synop. 1986, No. 2, in 48 pages, discloses the method for utilizing microorganism 3-carbonyl steroid to be changed into 3-carbonyl-7-alcohol steroid.In addition, for example, at Appl.Environ.Microbiol., 1982,44 volumes in 6 pages, disclose and have utilized microorganism 5 β-3-hydroxyl steroid to be changed into 5 β-3, the method for 7-dihydroxyl steroid.
In addition, as common vitochemical knowledge, as with two key oxidation rimose methods, known have a following method, for example, and via the epoxidation of two keys or two alcoholization and rimose method, rimose method and the direct cracking etc. that adopts ozone via ketone.
In addition, with courage steroid-5,7, the courage steroid-4,6 of 24-triolefin-3 β-when alcohol is raw material as intermediate, 24-triolefin-3-ketone is useful as the synthetic intermediate of various steroid class pharmaceuticals, but acquisition approach in the past is the raw material that comes from natural origin, and prepare through long reactions steps, therefore from cost and quantitative aspects, its application is restricted.For example, at Biochem.Biophys.Res.Commun., 1965,21 volumes, No. 2, in 149 pages, put down in writing following method, that is, and with courage steroid-5,24-diene-3-alcohol (ergot) carries out Ovshinsky oxidation (Oppenauer Oxidation), changes into 3-oxo-4, the 24-diene, carry out the enol etherificate again, change into 3-oxyethyl group-3,5, the 24-triolefin carries out the method that oxidation prepares by Manganse Dioxide again.
In addition, on the other hand, open in the 2004-141125 communique, put down in writing following method the spy, for example, metabolic engineering ground changes the Mycophyta of producing ergosterol via zymosterol, cultivates the variant of making, and takes from culture, prepare courage steroid-5,7 thus, 24-triolefin-3 β-alcohol.
Summary of the invention
The objective of the invention is to, provide a kind of preparation 3, the method for 7-dioxo-5 β-cholanic acid or its ester derivative, this method is with at 5 and 24 sterols with two keys, in further detail, with courage steroid-5,7,24-triolefin-3 β-alcohol or ergot steroid-5,7,24 (28)-triolefins-3 β-alcohol, desmosterol or fucosterol, ergot steroid-5,24 (28)-diene-3 β-alcohol are raw material, and through 4 following steps, that is:
(I) carry out the oxidation of 3 hydroxyls and 5 two keys to 4 isomerized step;
(II) cut off 24 steps that become carboxyl or its ester derivative by the oxidation of side chain;
(III) 7 steps that import oxygen functional group;
(IV) carry out the three-dimensional step that makes up of 5 β by the reduction saturation of 4 two keys.
In further detail, provide a kind of 3, the synthetic method of 7-dioxo-5 β-cholanic acid or its ester derivative, described 3,7-dioxo-5 β-cholanic acid or its ester derivative are a kind of at 3 and 7 compounds with oxygen functional group and 24 for carboxylic acid or ester, wherein, use courage steroid-5,7,24-triolefin-3 β-alcohol is raw material, and via courage steroid-4,6,24-triolefin-3-ketone.
For the raw material raw material in addition by same skeleton/same carbonatoms prepares 3 effectively, 7-dioxo-5 β-cholanic acid or its ester derivative, preferred use can make up the steroid class raw material of same side chain carbon atom number with step still less.Therefore, if 24 steroid classes, then can import 24 carboxyls or its ester derivative by the oxidation cracking with two keys.
In addition, if at 5 3-sterols, can make up 5 β solids by the reduction saturation again through of the isomerization of the two keys of 3 oxidations and 5 to 4 with two keys.
In addition, to 7 importing oxygen functional groups, if 3-oxo-4,6-diene steroid class then can be with 6 double bond epoxidations, if 3-oxo-4-alkene steroid class or 3-oxo steroid class and 3-hydroxyl steroid class then can utilize microorganism to carry out 7 hydroxylations.
In order to solve above-mentioned problem, what the inventor etc. furtherd investigate found that, for example, with courage steroid-5,7,24-triolefin-3 β-alcohol can at first carry out courage steroid-5 during as raw material, 7,24-triolefin-3 β-alcohol then makes 7 double-bond isomerisms change into 6 two keys, thereby obtains 3-ketone-4 to the isomerization to 4 of the oxidation of 3 ketoboidies and 5 two keys, 6, the 24-triene compound.
Find in addition, with courage steroid-4,6,6 and 24 double bond epoxidation of 24-triolefin-3-ketone, the reduction of then carrying out 4 saturation of double bondsization of being undertaken by hydrogenation and 6 carbon-oxygen bonds cuts off and 5 β spatial make up, carry out 24 again, 25 epoxies are to 24, the hydrolysis of 25-glycol, then carrying out 7 hydroxyls ftractures to the oxidation of ketone with to the oxidation of 24-carboxylic acid, according to circumstances again the 24-carboxylic acid is carried out esterification, can synthesize thus as the synthetic intermediate of various steroid classes such as Ursodeoxycholic Acid (UDCA) or gallodesoxycholic acid useful 3,7-dioxo-5 β-cholanic acid and ester derivative thereof.
Find in addition, after the epoxidation of two keys of in above-mentioned reaction 6 and 24, the order of change reaction, at first only with 24 epoxy hydrolysis, be converted into glycol, and then carry out hydrogenation and 4 saturation of double bondsization of 6 epoxies, can synthesize 3 equally, 7-dioxo-5 β-cholanic acid and ester derivative thereof.
Also find in addition, only with courage steroid-4,6,24 of 24-triolefin-3-ketone are carried out epoxidation, and hydrolysis is converted into glycol, again with 6 double bond epoxidation, carry out the hydrogenation of 6 epoxies and 4 saturation of double bondsization and 7 hydroxyls then to the oxidation of ketone and to the oxidation cracking of 24-carboxylic acid, according to circumstances again with the 24-carboxylic esterification, thus, can synthesize 3 equally, 7-dioxo-5 β-cholanic acid and ester derivative thereof.
Also find in addition, the hydrogenation of 6 epoxies in above-mentioned reaction and 4 saturation of double bondsization are carried out the oxidation of 7 hydroxyls afterwards, again with 24 epoxy hydrolysis, carry out oxidation cracking then to the 24-carboxylic acid, according to circumstances again with the 24-carboxylic esterification, thus, can synthesize 3 equally, 7-dioxo-5 β-cholanic acid and ester derivative thereof.
Therefore, by above discovery, find by courage steroid-5 to have the sterols of two keys at 5 and 24,7,24-triolefin-3 β-alcohol or ergot steroid-5,7,24 (28)-triolefins-3 β-alcohol, desmosterol or fucosterol, ergot steroid-5,24 (28)-diene-3 β-alcohol is raw material, and 4 steps through following can prepare 3,7-dioxo-5 β-cholanic acid or its ester derivative, so that finish the present invention, described 4 steps are:
(I) carry out the oxidation of 3 hydroxyls and 5 two keys to 4 isomerized step;
(II) cut off 24 steps that become carboxyl or its ester derivative by the oxidation of side chain;
(III) 7 steps that import oxygen functional group;
(IV) carry out the three-dimensional step that makes up of 5 β by the reduction saturation of 4 two keys.
The sketch chart of above-mentioned (I)～(IV) below is shown.
Figure A20058003063000261
(in the formula, A 1Expression hydrogen atom or sec.-propyl, A 2, A 3Independent separately, A 1Represent methyl during for hydrogen atom, A 1Represent hydrogen atom or methyl during for sec.-propyl, C I～C IIBetween key be singly-bound or two key).
Below, the sketch chart of above-mentioned (II) is shown.
Courage steroid-5,7,24-triolefin-3 β-pure ergot steroid-5,7,24 (28)-triolefins-3 β-alcohol
Fucosterol
Desmosterol ergot steroid-5,24 (28)-diene-3 β-alcohol
Figure A20058003063000271
(in the formula, St represents to comprise the steroid class skeleton of A ring, B ring, C ring and D ring, and this steroid class skeleton (1) combines with the side chain shown in the formula in the C17 position; (2) on A ring, B ring, C ring and D ring, can have hydroxyl, protected hydroxyl, ketone group or epoxy group(ing); (3) key that is selected between the carbon-to-carbon of one or more positions of C1 position～C8 position can have two keys; (4) the one or more positions that are selected from C4 position, C10 position, C13 position and the C14 position can be by methyl substituted).
That is,, provide the following described invention in (1)～(49) according to the present invention.
(1) following general formula (8), (21a), (21b), (21c) or (21d)
(in the formula, R 1The alkyl of expression hydrogen atom or carbonatoms 1～6) 3 of expression, 7-dioxo-5 β-cholanic acid (8), Ursodeoxycholic Acid (UDCA) (21a), gallodesoxycholic acid (21b) or 3 Alpha-hydroxies-7-oxo-5 β-cholanic acid (21c), the preparation method of 7-hydroxyl-3-oxo-5 β-cholanic acid (21d) or these sour ester derivatives, it is characterized in that, with the carbonatoms that generates from carbohydrate with fermentation method more than 22 the steroid of (preferred more than 24) as raw material, and comprising the step of carrying out the three-dimensional structure of 5 β, the three-dimensional structure by the reduction saturation of 4 two keys of described 5 β undertaken.
(2) following general formula (8), (21a), (21b), (21c) or (21d)
Figure A20058003063000281
(in the formula, R 1The alkyl of expression hydrogen atom or carbonatoms 1～6) 3 of expression, the preparation method of 7-dioxo-5 β-cholanic acid (8), Ursodeoxycholic Acid (UDCA) (21a), gallodesoxycholic acid (21b) or 3 Alpha-hydroxies-7-oxo-5 β-cholanic acid (21c), 7-hydroxyl-3-oxo-5 β-cholanic acid (21d) or these sour ester derivatives, it is characterized in that, or (A8) at following general formula (A1), (A2), (A3), (A4), (A5), (A6), (A7)
Figure A20058003063000291
(in the formula, A 1Expression hydrogen atom or sec.-propyl, A 2, A 3Independent separately, A 1Represent methyl during for hydrogen atom, A 1Represent hydrogen atom or methyl during for sec.-propyl, B 1, B 2And B 3Independent separately, expression hydroxyl or protected hydroxyl, n represents 0 or 1 integer) in the steroid of expression, carry out that 5 β are three-dimensional to be made up, the three-dimensional structure by the reduction saturation of 4 two keys of described 5 β undertaken.
(3) the following general formula (8) described in above-mentioned (2), (21a), (21b), (21c) or (21d)
(in the formula, R 1The alkyl of expression hydrogen atom or carbonatoms 1～6) 3 of expression, the preparation method of 7-dioxo-5 β-cholanic acid (8), Ursodeoxycholic Acid (UDCA) (21a), gallodesoxycholic acid (21b) or 3 Alpha-hydroxies-7-oxo-5 β-cholanic acid (21c), 7-hydroxyl-3-oxo-5 β-cholanic acid (21d) or these sour ester derivatives, it is characterized in that following general formula (A1), (A2), (A3), (A4), (A5), (A6), (A7) or (A8)
Figure A20058003063000302
Figure A20058003063000311
(in the formula, A 1Expression hydrogen atom or sec.-propyl, A 2, A 3Independent separately, A 1Represent methyl during for hydrogen atom, A 1Represent hydrogen atom or methyl during for sec.-propyl, B 1, B 2And B 3Independent separately, expression hydroxyl or protected hydroxyl, n represents 0 or 1 integer) be by following general formula (1)
Figure A20058003063000312
(in the formula, A 1Expression hydrogen atom or sec.-propyl, A 2, A 3Independent separately, at A 1Represent methyl during for hydrogen atom, A 1Represent hydrogen atom or methyl during for sec.-propyl, C I～C IIBetween key be singly-bound or two key) expression sterol compound deutero-material.
(4) following general formula (8), (21a), (21b), (21c) or (21d)
Figure A20058003063000321
(in the formula, R 1The alkyl of expression hydrogen atom or carbonatoms 1～6) 3 of expression, the preparation method of 7-dioxo-5 β-cholanic acid (8), Ursodeoxycholic Acid (UDCA) (21a), gallodesoxycholic acid (21b) or 3 Alpha-hydroxies-7-oxo-5 β-cholanic acid (21c), 7-hydroxyl-3-oxo-5 β-cholanic acid (21d) or these sour ester derivatives, wherein, with following general formula (1)
Figure A20058003063000322
(in the formula, A 1Expression hydrogen atom or sec.-propyl, A 2, A 3Independent separately, at A 1Represent methyl during for hydrogen atom, A 1Represent hydrogen atom or methyl during for sec.-propyl, C I～C IIBetween key be singly-bound or two key) sterol compound of expression is raw material, and comprise the steps:
(I) carry out the oxidation of 3 hydroxyls and 5 two keys to 4 isomerized step;
(II) cut off 24 steps that change into carboxyl or its ester derivative by the oxidation of side chain;
(III) 7 steps that import oxygen functional group; And
(IV) carry out the three-dimensional step that makes up of 5 β by the reduction saturation of 4 two keys.
(5) the following general formula (8) described in above-mentioned (4), (21a), (21b), (21c) or (21d)
Figure A20058003063000331
(in the formula, R 1The alkyl of expression hydrogen atom or carbonatoms 1～6) 3 of expression, the preparation method of 7-dioxo-5 β-cholanic acid (8), Ursodeoxycholic Acid (UDCA) (20a), gallodesoxycholic acid (20b) or 3 Alpha-hydroxies-7-oxo-5 β-cholanic acid (20c), 7-hydroxyl-3-oxo-5 β-cholanic acid (20d) or these sour ester derivatives, wherein, following general formula (1)
Figure A20058003063000332
(in the formula, A 1Expression hydrogen atom or sec.-propyl, A 2, A 3Independent separately, at A 1Represent methyl during for hydrogen atom, A 1Represent hydrogen atom or methyl during for sec.-propyl, C I～C IIBetween key be singly-bound or two key) expression sterol compound be courage steroid-5,7,24-triolefin-3 β-alcohol or ergot steroid-5,7,24 (28)-triolefins-3 β-alcohol, desmosterol or fucosterol, ergot steroid-5,24 (28)-diene-3 β-alcohol.
(6) the following general formula (8) described in above-mentioned (4), (21a), (21b), (21c) or (21d)
Figure A20058003063000341
(in the formula, R 1The alkyl of expression hydrogen atom or carbonatoms 1～6) 3 of expression, the preparation method of 7-dioxo-5 β-cholanic acid (8), Ursodeoxycholic Acid (UDCA) (21a), gallodesoxycholic acid (21b) or 3 Alpha-hydroxies-7-oxo-5 β-cholanic acid (21c), 7-hydroxyl-3-oxo-5 β-cholanic acid (21d) or these sour ester derivatives, wherein, following general formula (1)
Figure A20058003063000342
(in the formula, A 1Expression hydrogen atom or sec.-propyl, A 2, A 3Independent separately, at A 1Represent methyl during for hydrogen atom, A 1Represent hydrogen atom or methyl during for sec.-propyl, C I～C IIBetween key be singly-bound or two key) expression sterol compound be courage steroid-5,7,24-triolefin-3 β-alcohol.
(7) following formula (4)
Figure A20058003063000343
The courage steroid-4,6 of expression, the preparation method of 24-triolefin-3-ketone is characterized in that, with following formula (2)
The courage steroid-5,7 of expression, 24-triolefin-3 β-pure oxidation changes into following formula (3)
Figure A20058003063000352
The courage steroid-4,7 of expression, 24-triolefin-3-ketone then carries out isomerization.
(8) the courage steroid-4,6 described in above-mentioned (7), the preparation method of 24-triolefin-3-ketone is characterized in that, carries out oxidizing reaction in the presence of ketone compound and metal alkoxide.
(9) the courage steroid-4,6 described in above-mentioned (8), the preparation method of 24-triolefin-3-ketone is characterized in that, carries out oxidizing reaction under the situation of isolation from oxygen.
(10) the courage steroid-4,6 described in above-mentioned (8), the preparation method of 24-triolefin-3-ketone is characterized in that, the ketone compound general formula R 2(C=O) R 3(in the formula, R 2And R 3Chain or the cyclic alkyl of representing carbonatoms 1～10 respectively independently also can R 2And R 3Mutually combine and form the ring texture of carbonatoms 3～8) expression.
(11) the courage steroid-4,6 described in above-mentioned (7), the preparation method of 24-triolefin-3-ketone is characterized in that, carries out isomerization reaction in the presence of basic cpd.
(12) the courage steroid-4,6 described in above-mentioned (11), the preparation method of 24-triolefin-3-ketone is characterized in that, basic cpd is oxyhydroxide, carbonate or the alkoxide of basic metal or alkaline-earth metal.
(13) the courage steroid-4,6 described in above-mentioned (11), the preparation method of 24-triolefin-3-ketone is characterized in that, carries out isomerization reaction under the situation of isolation from oxygen.
(14) following formula (3)
Figure A20058003063000353
The courage steroid-4,7 of expression, 24-triolefin-3-ketone.
(15) a kind of 3-oxo-4, the preparation method of 7-diene steroid is characterized in that, as with following general formula (2a), (2b), (2c), (2d), (2e)
(in the formula, R 4～R 8Independent separately; expression hydrogen atom, protected hydroxyl or halogen atom; perhaps can be by alkyl, alkenyl or the alkynyl of the carbonatoms 1～10 of carbonyl, ether, protected hydroxyl, halogen atom or carboxyl substituted) the 3-hydroxyl-5 of expression, 7-diene steroid is oxidized to following general formula (3a), (3b), (3c), (3d), (3e)
Figure A20058003063000362
(in the formula, R 4～R 8Independent separately; expression hydrogen atom, protected hydroxyl or halogen atom; perhaps can be by carbonyl, ether, protected hydroxyl, by alkyl, alkenyl or the alkynyl of the carbonatoms 1～10 of halogen atom or carboxyl substituted) method of the compound of expression, carrying out under the situation of isolation from oxygen and in the presence of ketone compound and metal alkoxide.
(16) a kind of 3-oxo-4, the preparation method of 6-diene steroid is characterized in that, is catalyzer with alkali, respectively with following general formula (3a), (3b), (3c), (3d), (3e)
(in the formula, R 4～R 8Independent separately; expression hydrogen atom, hydroxyl, protected hydroxyl or halogen atom; perhaps can be by alkyl, alkenyl or the alkynyl of the carbonatoms 1～10 of carbonyl, ether, hydroxyl, protected hydroxyl, halogen atom or carboxyl substituted) the 3-oxo-4 of expression, 7-diene steroid is isomerizated into following formula (4a), (4b), (4c), (4d), (4e)
Figure A20058003063000372
(in the formula, R 4～R 8Independent separately, expression hydrogen atom, hydroxyl, protected hydroxyl or halogen atom perhaps can be by alkyl, alkenyl or the alkynyls of the carbonatoms 1～10 of carbonyl, ether, hydroxyl, protected hydroxyl, halogen atom or carboxyl substituted) compound of expression.
(17) following general formula (8)
Figure A20058003063000381
(in the formula, R 1The alkyl of expression hydrogen atom or carbonatoms 1～6) 3 of expression, the preparation method of 7-dioxo-5 β-cholanic acid or its ester derivative is characterized in that, with following formula (4)
Figure A20058003063000382
The courage steroid-4,6 of expression, 24-triolefin-3-ketone epoxy changes into following formula (5)
Figure A20058003063000383
6 of expression, 7:24,25-diepoxy courage steroid-4-alkene-3-ketone then carries out hydrogenation, changes into following formula (6)
Figure A20058003063000384
5 β-24 of expression, 25-epoxy courage steroid-3-ketone-7-alcohol is hydrolyzed again, changes into following formula (7)
5 β-courage steroid-3-the ketone-7,24 of expression, the 25-triol carries out oxidation again, according to circumstances carries out esterification again.
(18) following general formula (8)
(in the formula, R 1The alkyl of expression hydrogen atom or carbonatoms 1～6) 3 of expression, the preparation method of 7-dioxo-5 β-cholanic acid or its ester derivative is characterized in that, with following formula (4)
The courage steroid-4,6 of expression, 24-triolefin-3-ketone epoxy changes into following formula (5)
Figure A20058003063000392
6 of expression, 7:24,25-diepoxy courage steroid-4-alkene-3-ketone then is hydrolyzed, and changes into following formula (9)
Figure A20058003063000393
6 of expression, 7-epoxy courage steroid-4-alkene-3-ketone-24, the 25-glycol carries out hydrogenation again, changes into following formula (7)
5 β-courage steroid-3-the ketone-7,24 of expression, the 25-triol carries out oxidation again, according to circumstances carries out esterification again.
(19) following general formula (8)
Figure A20058003063000395
(in the formula, R 1The alkyl of expression hydrogen atom or carbonatoms 1～6) 3 of expression, the preparation method of 7-dioxo-5 β-cholanic acid or its ester derivative is characterized in that, with following formula (4)
The courage steroid-4,6 of expression, 24-triolefin-3-ketone epoxy changes into following formula (10)
Figure A20058003063000397
24 of expression, 25-epoxy courage steroid-4,6-diene-3-ketone then is hydrolyzed, and changes into following formula (11)
Figure A20058003063000401
The courage steroid-4 of expression, 6-diene-3-ketone-24, the 25-glycol then carries out epoxidation, changes into following formula (9)
Figure A20058003063000402
6 of expression, 7-epoxy courage steroid-4-alkene-3-ketone-24, the 25-glycol carries out hydrogenation again, changes into following formula (7)
Figure A20058003063000403
5 β-courage steroid-3-the ketone-7,24 of expression, the 25-triol carries out oxidation again, according to circumstances carries out esterification again.
(20) following general formula (8)
Figure A20058003063000404
(in the formula, R 1The alkyl of expression hydrogen atom or carbonatoms 1～6) 3 of expression, the preparation method of 7-dioxo-5 β-cholanic acid or its ester derivative is characterized in that, with following formula (4)
Figure A20058003063000405
The courage steroid-4,6 of expression, 24-triolefin-3-ketone epoxy changes into following formula (5)
Figure A20058003063000406
6 of expression, 7:24,25-diepoxy courage steroid-4-alkene-3-ketone then carries out hydrogenation, changes into following formula (6)
Figure A20058003063000411
5 β-24 of expression, 25-epoxy courage steroid-3-ketone-7-alcohol carries out oxidation again, changes into following formula (12)
Figure A20058003063000412
5 β-24 of expression, 25-epoxy courage steroid-3, the 7-glycol then is hydrolyzed, and changes into following formula (13)
Figure A20058003063000413
5 β-courage the steroid-3 of expression, 7-diketone-24, the 25-glycol carries out oxidation again, according to circumstances carries out esterification again.
(21) each is described 3 in above-mentioned (17)～(20), and the preparation method of 7-dioxo-5 β-cholanic acid or its ester derivative is characterized in that, as epoxidizing agent, uses organo-peroxide.
(22) 3 described in above-mentioned (21), the preparation method of 7-dioxo-5 β-cholanic acid or its ester derivative is characterized in that, as organo-peroxide, uses general formula A 4CO 3H (in the formula, A 4The alkyl that can be replaced by halogen atom of expression hydrogen atom, carbonatoms 1～20, maybe can have substituent aryl) percarboxylic acids or the general formula A of expression 5(C=NH) OOH (in the formula, A 5The alkyl of expression hydrogen atom, the carbonatoms 1～20 that can be replaced by halogen atom, maybe can have substituent aryl) expression cross imines carboxylic acid or following general formula (14)
Figure A20058003063000414
(in the formula, A 6And A 7Represent the alkyl that can be replaced by halogen of carbonatoms 1～20 respectively independently, perhaps also can A 6And A 7Ring texture in conjunction with formation carbonatoms 3～8) ketone peroxide (dioxirane) derivative of expression.
(23) 3 described in above-mentioned (21), the preparation method of 7-dioxo-5 β-cholanic acid or its ester derivative is characterized in that, as organo-peroxide, uses peroxybenzoic acid or 2-methyl peroxybenzoic acid.
(24) 3 described in above-mentioned (23), the preparation method of 7-dioxo-5 β-cholanic acid or its ester derivative is characterized in that, adds water in epoxidation reaction.
(25) 3 described in above-mentioned (23), the preparation method of 7-dioxo-5 β-cholanic acid or its ester derivative is characterized in that, mistake acid concentration and carboxylic acid concentration during with epoxidation reaction remain on below the 0.3M.
(26) each is described 3 in above-mentioned (17), (18) or (20), and the preparation method of 7-dioxo-5 β-cholanic acid or its ester derivative is characterized in that, with following formula (4)
Figure A20058003063000421
The courage steroid-4,6 of expression, 24-triolefin-3-ketone halo esterification (halo-esterifying) changes into following formula (15)
Figure A20058003063000422
7 of (in the formula, X represents halogen atom, and Y represents the alkyl that can be replaced by halogen of hydrogen atom or carbonatoms 1～10) expression, 24-halo-courage steroid-3-ketone-6, the 25-diol diesters then carries out the basic hydrolysis and the Guan Huan of ester, changes into following formula (5)
Figure A20058003063000423
6 of expression, 7:24,25-diepoxy courage steroid-4-alkene-3-ketone.
(27) above-mentioned (26) described 3, the preparation method of 7-dioxo-5 β-cholanic acid or its ester derivative, it is characterized in that, as the halo esterifying agent, use the halogen positively charged ion propellant of organic carboxyl acid and general formula Z-X (X represents halogen atom in the formula, and Z represents succinimide, phthalic imidine, ethanamide, glycolylurea, tert.-butoxy) expression.
(28) each is described 3 in above-mentioned (17)～(20) and (26), and the preparation method of 7-dioxo-5 β-cholanic acid or its ester derivative is characterized in that, carries out hydrogenation in the presence of noble metal catalyst.
(29) above-mentioned (28) described 3, the preparation method of 7-dioxo-5 β-cholanic acid or its ester derivative, it is characterized in that, as noble metal catalyst, use one or two or more kinds the palladium metal be selected from active carbon-supported palladium, alumina load palladium, barium carbonate supported palladium, barium sulfate supported palladium or the lime carbonate supported palladium that pulverous palladium or palladium content are 0.5～50 weight %.
(30) above-mentioned (28) or (29) are described 3, and the preparation method of 7-dioxo-5 β-cholanic acid or its ester derivative is characterized in that, in the hydrogenation in the presence of the noble metal catalyst, has alkali simultaneously.
(31) above-mentioned (30) are described 3, and the preparation method of 7-dioxo-5 β-cholanic acid or its ester derivative is characterized in that, as alkali, use amine.
(32) each is described 3 in above-mentioned (17)～(20) and (26), and the preparation method of 7-dioxo-5 β-cholanic acid or its ester derivative is characterized in that, carries out the hydrolysis reaction of epoxy in the presence of silica gel or protonic acid.
(33) above-mentioned (32) described 3, the preparation method of 7-dioxo-5 β-cholanic acid or its ester derivative, it is characterized in that,, use hydrochloric acid, sulfuric acid, nitric acid, perchloric acid, phosphoric acid, phosphorous acid, Hypophosporous Acid, 50, organic carboxyl acid class or organic sulfonic acid class as protonic acid.
(34) in above-mentioned (17)～(20) and (26) each described 3, the preparation method of 7-dioxo-5 β-cholanic acid or its ester derivative, it is characterized in that, as the oxygenant of oxidizing reaction, use oxyhalogen acids (oxy-halogen acids) or its salt or molecular state halogen or permanganic acid class, dichromic acid class, chromic acid class.
(35) each is described 3 in above-mentioned (17)～(20) and (26), and the preparation method of 7-dioxo-5 β-cholanic acid or its ester derivative is characterized in that, as following formula (4)
Figure A20058003063000431
The courage steroid-4,6 of expression, 24-triolefin-3-ketone uses following formula (3)
Figure A20058003063000432
The courage steroid-4,7 of expression, 24-triolefin-3-ketone isomerization and the compound that obtains.
(36) above-mentioned (35) are described 3, and the preparation method of 7-dioxo-5 β-cholanic acid or its ester derivative is characterized in that, as following formula (3)
Figure A20058003063000433
The courage steroid-4,7 of expression, 24-triolefin-3-ketone uses following formula (2)
Figure A20058003063000441
The courage steroid-5,7 of expression, 24-triolefin-3 β-pure oxidation and the compound that obtains.
(37) following general formula (17)
Figure A20058003063000442
(in the formula, R 8Alkyl, alkenyl or the alkynyl of expression hydroxyl, protected hydroxyl, carboxyl, ester group, carbonyl, cyano group, amino or the carbonatoms 1～20 that can be replaced by halogen atom) preparation method of vicinal diol compound of expression; it is characterized in that; with silica gel as catalyzer, with following general formula (16)
Figure A20058003063000443
(in the formula, R 8Alkyl, alkenyl or the alkynyl of expression hydroxyl, protected hydroxyl, carboxyl, ester group, carbonyl, cyano group, amino or the carbonatoms 1～20 that can be replaced by halogen atom) the epoxy compounds hydrolysis of expression.
(38) following general formula (19)
Figure A20058003063000444
(in the formula, St represents to comprise the steroid class skeleton of A ring, B ring, C ring and D ring, and this steroid class skeleton (1) combines with the side chain shown in the formula in the C17 position; (2) on A ring, B ring, C ring and D ring, can have hydroxyl, protected hydroxyl, ketone group or epoxy group(ing); (3) key that is selected between the carbon-to-carbon of one or more positions of C1 position～C8 position can have two keys; (4) the one or more positions that are selected from C4 position, C10 position, C13 position and the C14 position can be by methyl substituted.R 9Expression can have alkylidene group, alkenylene or the alkynylene of the carbonatoms 1～20 of hydroxyl, protected hydroxyl, carboxyl, ester group, carbonyl, cyano group, amino or halogen atom) preparation method of vicinal diol compound of expression; it is characterized in that; with silica gel as catalyzer, with following general formula (18)
Figure A20058003063000445
(in the formula, St represents to comprise the steroid class skeleton of A ring, B ring, C ring and D ring, and this steroid class skeleton (1) combines with the side chain shown in the formula in the C17 position; (2) on A ring, B ring, C ring and D ring, can have hydroxyl, protected hydroxyl, ketone group or epoxy group(ing); (3) key that is selected between the carbon-to-carbon of one or more positions of C1 position～C8 position can have two keys; (4) the one or more positions that are selected from C4 position, C10 position, C13 position and the C14 position can be by methyl substituted.R 9Expression can have alkylidene group, alkenylene or the alkynylene of the carbonatoms 1～20 of hydroxyl, protected hydroxyl, carboxyl, ester group, carbonyl, cyano group, amino or halogen atom) expression the hydrolysis of steroid class epoxy compounds.
(39) following formula (5)
Figure A20058003063000451
6 of expression, 7:24,25-diepoxy courage steroid-4-alkene-3-ketone.
(40) following formula (10)
Figure A20058003063000452
24 of expression, 25-epoxy courage steroid-4,6-diene-3-ketone.
(41) following formula (11)
The courage steroid-4 of expression, 6-diene-3-ketone-24,25-glycol.
(42) following formula (6)
5 β-24 of expression, 25-epoxy courage steroid-3-ketone-7-alcohol.
(43) following formula (7)
Figure A20058003063000461
5 β-courage steroid-3-the ketone-7,24 of expression, the 25-triol.
(44) following formula (9)
Figure A20058003063000462
6 of expression, 7-epoxy courage steroid-4-alkene-3-ketone-24,25-glycol.
(45) following formula (12)
Figure A20058003063000463
5 β-24 of expression, 25-epoxy courage steroid-3,7-diketone.
(46) following formula (13)
Figure A20058003063000464
5 β-courage the steroid-3 of expression, 7-diketone-24,25-glycol.
(47) following formula (15a)
7 of expression, 24-two chloro-courage steroids-4-alkene-3-ketone-6,25-glycol dicarboxylic acid esters.
(48) following formula (20)
Figure A20058003063000471
24 of expression, 25-epoxy courage steroid-4-alkene-3-ketone-7-alcohol.
(49) following general formula (21a), (21b), (21c) or (21d)
Figure A20058003063000472
(in the formula, R 1The alkyl of expression hydrogen atom or carbonatoms 1～6) preparation method of Ursodeoxycholic Acid (UDCA) (21a), gallodesoxycholic acid (21b) or 3 Alpha-hydroxies-7-oxo-5 β-cholanic acid (21c), 7-hydroxyl-3-oxo-5 β-cholanic acid (21d) or these sour ester derivatives of expression, it is characterized in that, will adopt the following general formula (8) of each described method preparation in above-mentioned (17)～(20), (26), (35) and (36)
Figure A20058003063000473
(in the formula, R 1The alkyl of expression hydrogen atom or carbonatoms 1～6) 3 of expression, oxidation is according to circumstances carried out in 7-dioxo-5 β-cholanic acid or the reduction of its ester derivative again.
Embodiment
Below, embodiments of the present invention are described in further detail.
Below, all wiring diagrams that comprise each reactions steps of the present invention are shown.
Figure A20058003063000481
Below, describe with reference to compound sequence number (2)～(15) shown in this wiring diagram.
The courage steroid-5,7 as raw material among the preparation method of the present invention, 24-triolefin-3 β-alcohol itself is known material.For example, can prepare by the following method, for example, metabolism engineering ground changes the Mycophyta of producing ergosterol via zymosterol, and cultivates the variant of making, and takes from culture again.For this preparation method's details, can reference example such as the spy opens flat 5-192184 communique, the spy opens the method for putting down in writing in the 2004-141125 communique.
＜step 1〉by the courage steroid-5,7 of following formula (2) expression, 24-triolefin-3 β-alcohol prepares the courage steroid-4,7 of following formula (3) expression, the step of 24-triolefin-3-ketone
Figure A20058003063000491
By above-mentioned reaction formula as can be known, step 1 of the present invention is to carry out courage steroid-5,7 simultaneously, and the oxidation of 3 hydroxyls of 24-triolefin-3 β-alcohol (following abbreviate as sometimes " compound 2 ") and 5 two keys are to 4 isomerized step.Known this step is by the transform method of ergosterol to ergot sterone (ergosteron), is called as " this Nore oxidation (Oppenauer Oxidation) difficult to understand ".
This oxidizing reaction uses metal alkoxide to carry out as hydrogen acceptor as catalyzer, use ketone compound.As metal alkoxide, for example, can use aluminum isopropylate, trimethyl carbinol aluminium, magnesium ethylate, magnesium propylate, titanium propanolate etc.As ketone compound, preferably use general formula R 2(C=O) R 3(in the formula, R 2And R 3Independent separately, the chain or the cyclic alkyl of expression carbonatoms 1～10 also can R 2And R 3Interosculate and form the ring texture of carbonatoms 3～8) compound of expression, particularly, can use chain ketone such as acetone, hexone, or cyclic ketone such as pimelinketone, cyclopentanone.Especially preferably use aluminum isopropylate as catalyzer, use pimelinketone or hexone as ketone compound.With respect to 1 mole " compound 1 ", the usage quantity of catalyzer is generally 0.1～20 mole, preferably uses about 0.2～0.5 mole.Under the situation of catalyst-free, react and carry out hardly, on the other hand, when catalyzer is too much,, therefore select from above-mentioned scope because side reaction is concurrent remarkable.With respect to 1 mole " compound 1 ", hydrogen acceptor uses 1～50 mole usually, preferably uses about 2～10 moles.
This reaction can be implemented down solvent-free, but also can use solvent.As such solvent, can use fat hydrocarbons such as hexane; Arenes such as toluene; Halogen kind solvents such as methylene dichloride; Ethers such as ether, tetrahydrofuran (THF); Non-proton property such as methyl-sulphoxide or dimethyl formamide polar solvent.As preferred solvent, use non-protonic solvent, be more preferably and use toluene or heptane.As temperature of reaction, select 90～130 ℃ usually, preferably select 100～120 ℃, the reaction times is about 1～3 hour.Reaction finishes postcooling to room temperature, adds entry and makes catalyst deactivation.The precipitation that filtration is separated out, and filtrate is concentrated, can obtain courage steroid-4,7 thus, 24-triolefin-3-ketone (compound 2) as object.Compound 2 can be further method such as be separated out by silica gel column chromatography or crystallization and is separated purification.
In addition, from the viewpoint of the stability of resultant, this reaction is preferably carried out under the situation of isolation from oxygen, for example, in advance solvent and ketone compound is carried out deoxidation treatment, is reflected under nitrogen or the argon atmosphere and carries out.Particularly, use, under the nitrogen atmosphere, react again the reduce pressure degassing and carry out the nitrogen method of replacement or carry out the nitrogen method of replacement of solvent and ketone compound by under nitrogen, carrying out reflux.
Isomerization reaction of the present invention also can similarly be applicable to as with following general formula (2a), (2b), (2c), (2d), (2e) of compound 2 similar compounds
(in the formula, R 4～R 8Independent separately; expression hydrogen atom, protected hydroxyl or halogen atom; perhaps can be by alkyl, alkenyl or the alkynyl of the carbonatoms 1～10 of carbonyl, ether, protected hydroxyl, halogen atom or carboxyl substituted) the 3-hydroxyl-5 of expression, 7-diene steroid.
That is, under the situation of isolation from oxygen, make these 3-hydroxyls-5,7-diene steroid reacts in the presence of ketone compound and metal alkoxide, can be oxidized to following general formula (3a), (3b), (3c), (3d), (3e) with high yield respectively
Figure A20058003063000511
(in the formula, R 4, R 6～R 8Independent separately, expression hydrogen atom, protected hydroxyl or halogen atom perhaps can be by alkyl, alkenyl or the alkynyls of the carbonatoms 1～10 of carbonyl, ether, protected hydroxyl, halogen atom or carboxyl substituted) compound of expression.
As the object lesson of above-mentioned compound (2a), can enumerate courage steroid-5,7,24-triolefin-3 β-alcohol or ergosterol.
＜step 2〉by the courage steroid-4,7 of following formula (3) expression, 24-triolefin-3-ketone prepares the courage steroid-4,6 of following formula (4) expression, the step of 24-triolefin-3-ketone
Figure A20058003063000512
By above-mentioned reaction formula as can be known, step 2 of the present invention is to carry out courage steroid-4,7, and 7 double-bond isomerisms of 24-triolefin-3-ketone (below, abbreviate " compound 3 " sometimes as) change into the step of 6 reaction.
Isomerization reaction is carried out as catalyzer with basic cpd.As such basic cpd, can use alkali metal hydroxide, alkaline earth metal hydroxides, alkaline carbonate, alkaline earth metal carbonate, alkali metal hydrocarbonate, alkali metal acetate, alkaline-earth metal acetate, alkali metal alcoholates or alkaline-earth alkoxides, the preferred alkali metal hydroxide that uses is more preferably and uses potassium hydroxide, sodium hydroxide.With respect to 1 mole " compound 2 ", the usage quantity of basic cpd is generally 1～20 mole, preferred about 2～10 moles.
Reaction solvent is not particularly limited, and can use fat hydrocarbons such as hexane; Arenes such as toluene; Halogen kind solvents such as methylene dichloride; Ethers such as ether, tetrahydrofuran (THF); Alcohols such as methyl alcohol, ethanol; Non-proton property such as methyl-sulphoxide or dimethyl formamide polar solvent preferably uses methyl alcohol.The reaction usually 40～80 ℃, preferably carrying out about 5～10 hours under 50～70 ℃.After specified time finishes, add acid and neutralize, reaction is stopped as the alkali of catalyzer.The acid of using is not particularly limited, and for example, can use mineral acids such as hydrochloric acid, sulfuric acid; Or organic carboxyl acids such as formic acid, acetate; Organic sulfonic acids such as tosic acid.After the neutralization, can under reduced pressure heat up in a steamer and desolvate, thus the courage steroid-4,6 of acquisition purpose resultant, 24-triolefin-3-ketone (below, abbreviate " compound 3 " sometimes as).According to circumstances, add entry in can the reaction solution after neutralizing treatment compound 3 crystallizations separated out, perhaps add organic solvent and extract, with this organic solvent wash mutually, dry, concentrate, separate purification by silica gel column chromatography or other method again.
In addition, from the viewpoint of the stability of matrix, this reaction is preferably implemented under the situation of isolation from oxygen, for example, in advance solvent is carried out deoxidation treatment, reacts under nitrogen or argon atmosphere again.Particularly, use, under the nitrogen atmosphere, react again the reduce pressure degassing and carry out the nitrogen method of replacement or carry out the nitrogen method of replacement of solvent by under nitrogen, carrying out reflux.
Isomerization reaction of the present invention also can similarly be applicable to as with following general formula (3a), (3b), (3c), (3d), (3e) of compound 3 similar compounds
Figure A20058003063000521
(in the formula, R 4～R 8Independent separately; expression hydrogen atom, hydroxyl, protected hydroxyl or halogen atom; perhaps can be by alkyl, alkenyl or the alkynyl of the carbonatoms 1～10 of carbonyl, ether, hydroxyl, protected hydroxyl, halogen atom or carboxyl substituted) the 3-oxo-4 of expression, 7-diene steroid.
That is, as catalyzer, respectively with these 3-oxos-4,7-diene steroid is isomerizated into following formula (4a), (4b), (4c), (4d), (4e) with alkali
Figure A20058003063000531
(in the formula, R 4～R 8Independent separately; expression hydrogen atom, hydroxyl, protected hydroxyl or halogen former in; perhaps can be by alkyl, alkenyl or the alkynyl of the carbonatoms 1～10 of carbonyl, ether, hydroxyl, protected hydroxyl, halogen atom or carboxyl substituted) the 3-oxo-4 of expression, 6-diene steroid.
As above-mentioned protected hydroxyl, can enumerate by ether is the hydroxyl etc. of blocking group protection.
＜step 3A〉by the courage steroid-4,6 of following formula (4) expression, 24-triolefin-3-ketone prepares 6 of following formula (5) expression, 7:24, the step of 25-diepoxy courage steroid-4-alkene-3-ketone
Figure A20058003063000532
By above-mentioned reaction formula as can be known, step 3 of the present invention is the steps of carrying out epoxidised reaction, and described epoxidation is with courage steroid-4,6, and 6 of 24-triolefin-3-ketone (below, abbreviate " compound 4 " sometimes as) and two keys of 24 carry out epoxidation.As epoxidizing agent, use organo-peroxide usually.
As organo-peroxide, can use general formula A 4CO 3H (in the formula, A 4The alkyl of expression hydrogen atom, the carbonatoms 1～20 that can be replaced by halogen, maybe can have substituent aryl) percarboxylic acids or the general formula A of expression 5(C=NH) OOH (in the formula, A 5The alkyl of expression hydrogen atom, the carbonatoms 1～20 that can be replaced by halogen, maybe can have substituent aryl) expression cross imidic acid or following general formula (14)
Figure A20058003063000541
(in the formula, A 6And A 7Independent separately, the alkyl that can be replaced by halogen of expression carbonatoms 1～20 perhaps also can A 6And A 7Mutually combine and form the ring texture of carbonatoms 3～8) ketone peroxide (dioxirane) derivative of expression.Particularly,, peroxyformic acid, peracetic acid, perpropionic acid, peroxybenzoic acid, 2-methyl peroxybenzoic acid, monoperphthalic acid etc. can be enumerated,, CH can be enumerated as crossing imidic acid as percarboxylic acids 3(=NH) OOH (peroxide ethanimidic acid (Peroxyacetimidic acid)) etc. in addition, as the ketone peroxide derivative, can enumerate dimethyl ketone peroxide (acetone peroxide), methylethyl ketone peroxide (methylethyl ketone peroxide) etc. to C.
From reaction selection rate aspect, especially preferably use peroxybenzoic acid, 2-methyl peroxybenzoic acid.
With respect to 1 mole " compound 4 ", the usage quantity of organo-peroxide is generally 2～10 molar equivalents, preferred 2～3 molar equivalents.Epoxidised temperature usually from 0～100 ℃, preferably select from 40～90 ℃ scope.
Reaction solvent is not particularly limited, and can use fat hydrocarbons such as hexane; Arenes such as toluene; Halogen kind solvents such as methylene dichloride; Ethers such as ether, tetrahydrofuran (THF); Ester such as ethyl acetate or butylacetate class; Nitriles such as acetonitrile; Alcohols such as methyl alcohol, ethanol; Non-proton property such as methyl-sulphoxide or dimethyl formamide polar solvent; And water.Preferred ester class.In addition, percarboxylic acids during as oxygenant, particularly, by adding water or keeping mistake acid concentration and carboxylic acid concentration in the reaction solution low, can be significantly improved reaction preference.
Obtain 6,7:24,25-diepoxy courage steroid-4-alkene-3-ketone (compound 5) can adopt that silica gel column chromatography or crystallization are separated out etc., and method is separated purification.
＜step 3B〉by the courage steroid-4,6 of following formula (4) expression, 24-triolefin-3-ketone prepares 24 of following formula (10) expression, 25-epoxy courage steroid-4, the step of 6-diene-3-ketone
By above-mentioned reaction formula as can be known, step 3B of the present invention is the step of carrying out epoxidised reaction, and described epoxidation is with courage steroid-4,6, and two keys of 24 of 24-triolefin-3-ketone (below, abbreviate " compound 4 " sometimes as) carry out epoxidation.
Epoxidation reaction among the step 3A is that two keys of 24 preferentially carry out epoxidation, and two keys of 6 carry out epoxidation then.Therefore, the usage quantity of epoxidizing agent when perhaps temperature of reaction is low, obtains just 24 the two keys shown in the formula (10) and carries out epoxidised mono-epoxy compounds after a little while.Therefore, for example, can make the usage quantity of epoxidizing agent is 1 mole with respect to 1 mole " compound 4 ", and reacts near room temperature 1～3 hour.Other reaction conditions is identical with step 3A.
＜step 3C〉by the courage steroid-4 of following formula (11) expression, 6-diene-3-ketone-24,25-glycol prepare 6 of following formula (9) expression, 7-epoxy courage steroid-4-alkene-3-ketone-24, the step of 25-glycol
Figure A20058003063000551
By above-mentioned reaction formula as can be known, step 3C of the present invention is the step of carrying out epoxidised reaction, and described epoxidation is with courage steroid-4,6-diene-3-ketone-24, and two keys of 6 of 25-glycol (compound 11) carry out epoxidation.
At 3-ketone-4, two keys of 6 of 6-diene-steroid carry out on this aspect of epoxidation reaction, are the reactions same with above-mentioned steps 3A.Therefore, can use oxygenant and the solvent same with the situation of step 3A, reaction conditions is also identical, but with respect to 1 mole " compound 11 ", the usage quantity of epoxidizing agent is preferably 1～2 molar equivalent.
＜step 7〉by the courage steroid-4,6 of following formula (4) expression, 24-triolefin-3-ketone prepares 6 of following formula (5) expression, 7:24, the step of 25-diepoxy courage steroid-4-alkene-3-ketone
Figure A20058003063000552
(in the formula, X represents halogen atom, and Y represents the alkyl that can be replaced by halogen of hydrogen atom or carbonatoms 1～10).
Shown in above-mentioned formula, as other the method that obtains above-mentioned diepoxide (5), can also be via halogen ester, the hydrolysis of recombinant ester becomes the method for epoxide group with Guan Huan.
In the halo esterification, use organic carboxyl acid and general formula Z-X (in the formula, X represents halogen atom, Z represents succinimide, phthalic imidine, ethanamide, glycolylurea, tert.-butoxy etc.) expression halogen positively charged ion propellant, the preferred formic acid that uses uses t-butyl hypochlorite's salt as halogen positively charged ion propellant as organic carboxyl acid.
With respect to 1 mole " compound 4 ", the usage quantity of organic carboxyl acid is generally 2～50 moles, preferred 2～10 moles.With respect to 1 mole " compound 4 ", the usage quantity of halogen positively charged ion propellant is generally 2～10 moles, preferred 2～5 moles.
Usually carry out in the scope of 0～50 ℃ of temperature of reaction, preferably carry out 0～30 ℃ scope.As reaction solvent, can use fat hydrocarbons such as hexane; Arenes such as toluene; Halogen kind solvents such as methylene dichloride; Ethers such as ether, tetrahydrofuran (THF); Ester such as ethyl acetate or butylacetate class; Nitriles such as acetonitrile; Ketones such as acetone; Organic carboxyl acid such as acetate or formic acid class.
In addition, become in the epoxide group with Guan Huan, use alkali in the hydrolysis of the ester of the halogen ester that obtains.As alkali, can use oxyhydroxide, carbonate or the alkoxide of basic metal or alkaline-earth metal, with respect to 1 mole " compound 15 ", its usage quantity is generally 2～50 moles, is preferably 4～10 moles.Usually carry out in the scope of 0～50 ℃ of temperature of reaction, preferably carry out 0～30 ℃ scope.As reaction solvent, be not particularly limited, but preferably use nitrile, water such as ketones such as alcohols such as methyl alcohol or ethanol, acetone or acetonitrile.
＜step 4A〉by 6 of following formula (5) expression, 7:24,25-diepoxy courage steroid-4-alkene-3-ketone prepare 5 β-24 of following formula (6) expression, the step of 25-epoxy courage steroid-3-ketone-7-alcohol
Figure A20058003063000561
By above-mentioned reaction formula as can be known, step 4A of the present invention carries out 6,7:24, the hydrogenation (reduction) of 4 two keys of 25-diepoxy courage steroid-4-alkene-3-ketone (compound 5) and the reduction rimose step of 6 carbon-oxygen bonds.Hydrogenation is to use hydrogen to carry out in the presence of noble metal catalysts such as palladium, platinum, ruthenium.For example, as palladium catalyst, can use Powdered palladium or palladium content is active carbon-supported palladium, alumina load palladium, barium carbonate supported palladium, barium sulfate supported palladium or the lime carbonate supported palladium etc. of 0.5～50 weight %.With respect to 1 mole " compound 5 ", noble metal catalyst uses about 0.005～0.5 mole usually.Though the pressure of hydrogen is not particularly limited, under the pressure below the 1MPa, react usually.Solvent can use alcohols, ethers, ester class, aliphatics or arene etc., but is not to be defined as these materials especially.From viewpoint optionally, preferably in this reaction, there is alkali simultaneously, as alkali, amines such as preferred pyridine or triethylamine, Tetramethyl Ethylene Diamine, Diisopropylamine.With respect to 1 mole " compound 5 ", the usage quantity of alkali is used about 0.1～100 mole usually.Though carry out preferred 0～20 ℃ scope in the scope of 0～50 ℃ of temperature of reaction usually.
5 β-24 that obtain, 25-epoxy courage steroid-3-ketone-7-alcohol (compound 6) can be behind filtering catalysts, method such as separate out by silica gel column chromatography or crystallization and separate purification.
＜step 5A〉by 5 β-24 of following formula (6) expression, 25-epoxy courage steroid-3-ketone-7-alcohol prepares the 5 β-courage steroid-3-ketone-7,24 of following formula (7) expression, the step of 25-triol
By above-mentioned reaction formula as can be known, step 5A of the present invention carries out 5 β-24, and 24,25 epoxide group of 25-epoxy courage steroid-3-ketone-7-alcohol (compound 6) is hydrolyzed into 24, the step of 25-vicinal glycol.
Hydrolysis reaction makes water react in the presence of catalyzer to carry out.As such catalyzer, can use protonic acid or silica gel.As protonic acid, can enumerate hydrochloric acid, sulfuric acid, nitric acid, perchloric acid, phosphoric acid, phosphorous acid, Hypophosporous Acid, 50, organic carboxyl acid class, organic sulfonic acid class etc.As temperature of reaction, usually 10～60 ℃, particularly at room temperature stir about 1～4 hour, if desired, can carry out in the alkali and separate object.
Reaction solvent is not particularly limited, and can use ester class, ethers, nitrile etc., for example, preferably uses ethyl acetate, tetrahydrofuran (THF), acetonitrile etc.Under the situation of protonic acid, be equivalent to per 1 mole " compound 6 ", the usage quantity of catalyzer is about 0.01～2 mole.The organic solvent solution that feeds compound 5 in gelatinous silicon-dioxide makes compound 5 absorption, and then feeds organic solvent, can obtain the compound 7 of 24,25 epoxide group hydrolysis of compound 5 thus.
5 β that obtain-courage steroid-3-ketone-7,24,25-triol (compound 7) can method such as separate out by silica gel column chromatography or crystallization and separate purification.
＜step 5B〉by 6 of following formula (5) expression, 7:24,25-diepoxy courage steroid-4-alkene-3-ketone prepare 6 of following formula (9) expression, 7-epoxy courage steroid-4-alkene-3-ketone-24, the step of 25-glycol
Figure A20058003063000572
By above-mentioned reaction formula as can be known, step 5B of the present invention carries out 6,7:24, and 24,25 epoxide group of 25-diepoxy courage steroid-4-alkene-3-ketone (compound 5) is hydrolyzed into 24, the step of 25-vicinal glycol.
On this aspect of hydrolysis reaction of the side chain epoxy of steroid, be the reaction same with above-mentioned steps 5A.Therefore, can use same catalyzer and solvent under the situation with step 5A, reaction conditions is also identical.
＜step 5C〉by 24 of following formula (10) expression, 25-epoxy courage steroid-4,6-diene-3-ketone prepare the courage steroid-4 of following formula (11) expression, 6-diene-3-ketone-24, the step of 25-glycol
By above-mentioned reaction formula as can be known, step 5C of the present invention carries out 24,25-epoxy courage steroid-4, and 24,25 epoxide group of 6-diene-3-ketone (compound 10) is hydrolyzed into 24, the step of 25-vicinal glycol.
On this aspect of hydrolysis reaction of the side chain epoxy of steroid, be the reaction same with above-mentioned steps 5A.Therefore, can use same catalyzer and solvent under the situation with step 5A, reaction conditions is also identical.
＜step 5D〉by 5 β-24 of following formula (12) expression, 25-epoxy courage steroid-3,7-diketone prepare the 5 β-courage steroid-3 of following formula (13) expression, 7-diketone-24, the step of 25-glycol
Figure A20058003063000582
By above-mentioned reaction formula as can be known, step 5D of the present invention carries out 5 β-24,25-epoxy courage steroid-3, and 24,25 epoxide group of 7-diketone (compound 12) is hydrolyzed into 24, the step of 25-vicinal glycol.
On this aspect of hydrolysis reaction of the side chain epoxy of steroid, be the reaction same with above-mentioned steps 5A.Therefore, can use same catalyzer and solvent under the situation with step 5A, reaction conditions is also identical.
＜step 4B〉by 6 of following formula (9) expression, 7-epoxy courage steroid-4-alkene-3-ketone-24,25-glycol prepare the 5 β-courage steroid-3-ketone-7,24 of following formula (7) expression, the step of 25-triol
Figure A20058003063000583
By above-mentioned reaction formula as can be known, step 4B of the present invention carries out 6,7-epoxy courage steroid-4-alkene-3-ketone-24, the hydrogenation (reduction) of 4 two keys of 25-glycol (compound 9) and the reduction rimose step of 6 carbon-oxygen bonds.
On this aspect of hydrogenation of 6,7 epoxide groups that steroid B encircles, be the reaction same with above-mentioned steps 4A.Therefore, can use same noble metal catalyst, alkali and solvent under the situation with step 4A, reaction conditions is also identical.
＜step 6A〉by the 5 β-courage steroid-3-ketone-7,24 of following formula (7) expression, the 25-triol prepares 3 of general formula (8) expression, the step of 7-dioxo-5 β-cholanic acid or its ester derivative
Figure A20058003063000591
By above-mentioned reaction formula as can be known, step 6A of the present invention carries out 5 β-courage steroid-3-ketone-7,24,24 of 25-triol, and the step of esterification is carried out in the oxidation of the oxidation of 25-glycol moiety cracking and 7 hydroxyls if desired again.
As oxygenant, can use the halogen of oxyhalogen acids or its salt or molecular state or permanganic acid class, dichromic acid class, chromic acid class.As the oxyhalogen acids, can use hypohalous acid, halous acid, hydracid or the high hydracid of chlorine, bromine, iodine.As its salt, can use alkaline earth salts such as an alkali metal salts such as lithium, potassium, sodium, calcium, magnesium.Preferred hypohalous acid or its salt are more preferably and use Losantin or clorox.In addition, as oxygenant, can use chlorine, bromine gas equimolecular attitude halogen.According to circumstances, can use oxyhalogen acids or its salt and molecular state halogen simultaneously.As the permanganic acid class, can use potassium permanganate, as the dichromic acid class, can use dichromic acid or its pyridinium salt, as chromic acid, can use chromic acid or its pyridinium salt.
This oxidizing reaction can followingly be carried out: in the presence of ketone, ester class, nitrile, ethers, halogenated aliphatic hydrocarbon class, halogenated aromatic hydro carbons equal solvent, it is 3～20 molar equivalents that use is equivalent to 1 mole " compound 7 ", be preferably the oxygenant of 3～6 molar equivalents, 0～100 ℃, preferably under 0～30 ℃, carry out.
With this method for oxidation obtain 3,7-dioxo-5 β-cholanic acid (in compound 8, R is the material of hydrogen atom) can method such as be separated out by silica gel column chromatography or crystallization and separate purification.
In addition, then, adopt known method to carry out the esterification of 24 carboxylic acids, derive for the ester derivative of monocarboxylic acid (in compound 8, R is the material of the alkyl of carbonatoms 1～6), with similarly above-mentioned, can method such as separate out by silica gel column chromatography or crystallization and separate purification.As the alcohol that uses in the esterification, can enumerate straight chain shapes such as methyl alcohol, ethanol, propyl carbinol, the trimethyl carbinol, hexalin, chain or cycloalcohol.Particular methanol wherein.As reaction conditions, can in alcohol, easily implement by in the presence of acid catalysts such as sulfuric acid, tosic acid, heating.In addition, can also in the organic solvent beyond the alcohol, adopt sulfuric acid dialkyl and alkali (for example salt of wormwood) to carry out esterification.
＜step 6B〉by 5 β-24 of following formula (6) expression, 25-epoxy courage steroid-3-ketone-7-alcohol prepares 5 β-24 of following formula (12) expression, 25-epoxy courage steroid-3, the step of 7-diketone
Figure A20058003063000601
By above-mentioned reaction formula as can be known, step 6B of the present invention carries out 5 β-24,7 steps that hydroxyl oxidize is a ketone of 25-epoxy courage steroid-3-ketone-7-alcohol (compound 6).
On this aspect of oxidizing reaction of ketone, is the reaction same with above-mentioned steps 6A at 7 hydroxyls of steroid.Therefore, can use same oxygenant and solvent under the situation with step 6A, reaction conditions is also identical, but with respect to 1 mole " compound 6 ", the amount of necessary oxygenant is 1～5 molar equivalent, preferred 1～2 molar equivalent.
＜step 6C〉by the 5 β-courage steroid-3 of following formula (13) expression, 7-diketone-24,25-glycol prepare 3 of general formula (8) expression, the step of 7-dioxo-5 β-cholanic acid or its ester derivative
By above-mentioned reaction formula as can be known, step 6C of the present invention carries out 5 β-courage steroid-3,7-diketone-24,24 of 25-glycol (compound 13), the oxidation rimose step of 25-glycol moiety.
At 24 of steroid, on this aspect of the oxidation cleacvage reaction of 25-glycol moiety, be the reaction same with above-mentioned steps 6A.Therefore, can use same oxygenant and solvent under the situation with step 6A, reaction conditions is also identical, but with respect to 1 mole " compound 13 ", the amount of necessary oxygenant is 3～10 molar equivalents, preferred 2～3 molar equivalents.
More than, for of the present invention 3, the preparation method of 7-dioxo-5 β-cholanic acid or its ester derivative is illustrated.
In addition, the hydrolysis reaction of epoxy of the present invention for record and narrate as step 5A by compound 6 to the conversion of compound 7 and as step 5B record and narrate by compound 5 to the conversion of compound 9 and be extremely effective by compound 12 to the conversion of compound 13 as recording and narrating to the conversion of compound 11 and as step 5D by compound 10 of recording and narrating of step 5C, in addition, can also similarly be applicable to following general formula (16)
Figure A20058003063000611
(in the formula, R 8Alkyl, alkenyl or the alkynyl of expression hydroxyl, protected hydroxyl, carboxyl, ester group, carbonyl, cyano group, amino or the carbonatoms 1～20 that can be replaced by halogen atom) epoxy compounds and the following general formula (18) of expression
(in the formula, St represents to comprise the steroid class skeleton of A ring, B ring, C ring and D ring, and this steroid class skeleton (1) combines with the side chain shown in the formula in the C17 position; (2) on A ring, B ring, C ring and D ring, can have hydroxyl, protected hydroxyl, ketone group or epoxy group(ing); (3) key that is selected between the carbon-to-carbon of one or more positions of C1 position～C8 position can have two keys; (4) the one or more positions that are selected from C4 position, C10 position, C13 position and the C14 position can be by methyl substituted.R 9Expression can have alkylidene group, alkenylene or the alkynylene of the carbonatoms 1～20 of hydroxyl, protected hydroxyl, carboxyl, ester group, carbonyl, cyano group, amino or halogen atom) expression steroid class epoxy compounds.
That is, above-mentioned epoxy compounds can be transformed into following general formula (17)
Figure A20058003063000613
(in the formula, R 8Alkyl, alkenyl or the alkynyl of expression hydroxyl, protected hydroxyl, carboxyl, ester group, carbonyl, cyano group, amino or the carbonatoms 1～20 that can be replaced by halogen atom) the vicinal diol compound of expression; in addition, above-mentioned steroid class epoxy compounds is transformed into following general formula (19)
Figure A20058003063000614
(in the formula, St represents to comprise the steroid class skeleton of A ring, B ring, C ring and D ring, and this steroid class skeleton (1) combines with the side chain shown in the formula in the C17 position; (2) on A ring, B ring, C ring and D ring, can have hydroxyl, protected hydroxyl, ketone group or epoxy group(ing); (3) key that is selected between the carbon-to-carbon of one or more positions of C1 position～C8 position can have two keys; (4) the one or more positions that are selected from C4 position, C10 position, C13 position and the C14 position can be by methyl substituted.R 9Expression can have alkylidene group, alkenylene or the alkynylene of the carbonatoms 1～20 of hydroxyl, protected hydroxyl, carboxyl, ester group, carbonyl, cyano group, amino or halogen atom) expression the vicinal diol compound.
As the epoxy compounds of above-mentioned general formula (16) expression, can enumerate for example by geraniol (citronello1) deutero-epoxy compounds; As the steroid class epoxy compounds of general formula (18) expression, can enumerate, for example 24,25-epoxy courage steroid-4,6-diene-3-ketone, 24,25-epoxy courage steroid-4-alkene-3-ketone etc.Method of the present invention is used in these epoxy compoundss, similarly can advantageously prepares the vicinal glycol.
By method of the present invention obtain 3,7-dioxo-5 β-cholanic acid or its ester derivative (compound 8) are the intermediates of steroid medicine.Compound 8 can be by reducing it with known method, is transformed into following general formula (21a), (21b), (21c) or (21d)
Figure A20058003063000621
(in the formula, R 1The alkyl of expression hydrogen atom or carbonatoms 1～6) Ursodeoxycholic Acid (UDCA) (21a), gallodesoxycholic acid (21b) or 3 Alpha-hydroxies-7-oxo-5 β-cholanic acid (21c), 7-hydroxyl-3-oxo-5 β-cholanic acid (21d) or these sour ester derivatives of expression.
As the reductive method, can enumerate, for example, with water, methyl alcohol, ethanol, tetrahydrofuran (THF) etc. as solvent, in the presence of catalyzer such as nickel (particularly drawing Buddhist nun's nickel), cobalt, copper/chromium, preferably under the coexistence of alkali such as sodium hydroxide, the method (catalytic hydrogenation method) of reacting with hydrogen; Perhaps in alcohol with the method (metallic reducing method) of basic metal reaction etc.In addition, can also use under near the extremely low temperature-45 ℃, be solvent with the tetrahydrofuran (THF), uses the method (using the hydride reduction method (hydride reduction method) of K-selectride) of specific organoboron compound etc.
For example, can utilize following reactions steps.
(1) 3,7-dioxo-5 β-cholanic acid → (metallic reducing or catalytic hydrogenation) → Ursodeoxycholic Acid (UDCA)
(2) 3,7-dioxo-5 β-cholanic acids → (catalytic hydrogenation) → 3 Alpha-hydroxies-7-oxo-5 β-cholanic acid
(3) 3 Alpha-hydroxies-7-oxo-5 β-cholanic acid → (metallic reducing) → Ursodeoxycholic Acid (UDCA)
(4) 3 Alpha-hydroxies-7-oxo-5 β-cholanic acid → (hydride reduction) → gallodesoxycholic acid
(5) gallodesoxycholic acid → (silver carbonate oxidation) → 7 Alpha-hydroxies-3-carbonyl-5 β-cholanic acid
For these methods, can open that clear 52-78863 communique, spy are opened clear 52-78864 communique, the spy opens clear 60-228500 communique, Tetrahedron (1984) 40 volumes with reference to the spy, No. 5,851 pages etc. record.
In addition, by 3,7-dioxo-5 β-cholanic acid or its ester derivative (compound 8) can be opened the record of clear 60-228500 communique and the flat 5-32692 communique of Te Kai with reference to the spy to the conversion of Ursodeoxycholic Acid (UDCA) or its ester derivative (21a).By 3,7-dioxo-5 β-cholanic acid or its ester derivative (compound 8) can be opened clear 52-78863 communique and special record of opening clear 52-78864 communique with reference to the spy to the conversion of 3 Alpha-hydroxies-7-oxo-5 β-cholanic acid or its ester derivative (21c).In addition, by 3 Alpha-hydroxies-7-oxo-5 β-cholanic acid or its ester derivative (21c) to the conversion of Ursodeoxycholic Acid (UDCA) or its ester derivative (21a) can open clear 52-78863 communique with reference to the spy, the spy opens clear 52-78864 communique and special record of opening flat 5-32692 communique.
Then, for above-mentioned sketch chart 1, embodiment is described in further detail.
With as the courage steroid-5,7 that has the sterols of two keys at 5 and 24,24-triolefin-3 β-alcohol or ergot steroid-5,7,24 (28)-triolefins-3 β-alcohol, desmosterol or fucosterol, ergot steroid-5,24 (28)-diene-3 β-alcohol are raw material, through 4 following steps, that is:
(I) carry out 3 the oxidation of hydroxyl and 5 two keys to 4 isomerized step
(II) cut off 24 steps that become carboxyl or its ester derivative by the oxidation of side chain
(III) 7 steps that import oxygen functional group
(IV) the reduction saturation of the two keys by 4 is carried out the three-dimensional step that makes up of 5 β and is prepared 3,7-dioxo-5 β-cholanic acid or its ester derivative, wherein,
For (I), at 5 sterols with two keys and in any one of 5,7 sterols with two keys, can be with for example implementing with the same method of above-mentioned steps 1.
In addition, for (III), for the steroid matrix that has two keys at 6, for example, can use the method enforcement same, in addition with above-mentioned steps 3A, 3B, 3C and step 7, for the steroid matrix that does not have two keys at 6, can use for example Appl.Environ.Microbiol., 1986,51 volumes, 946 pages or J.Chem.Res., Synop., 1986, No. 2,48 pages or Appl.Environ.Microbiol., 1982,44 volumes, the method for record is implemented in 6 pages.
In addition, for (IV), for example, can be with implementing with the same method of above-mentioned steps 4A, 4B.
In addition, at length (II) described based on above-mentioned sketch chart 2 below.
With courage steroid-5,7,24-triolefin-3 β-alcohol or desmosterol are under the situation of sterol of representative, for example, for the epoxidation of 24 two keys, can use the method enforcement same with above-mentioned steps 3A, 3B, then, being hydrolyzed into glycol by epoxy can be with for example implementing with the same method of above-mentioned steps 5A, 5B, 5C, 5D, and then, what the oxidation cracking by glycol carried out can be with for example implementing with the same method of above-mentioned steps 6A, 6C to the conversion of 24 carboxyls.
On the other hand, with ergot steroid-5,7,24 (28)-triolefins-3 β-alcohol, fucosterol, ergot steroid-5, under the situation of 24 (28)-diene-3 β-alcohol for the sterol of representative, for example, epoxidation for 24 (28) two keys, can use and above-mentioned steps 3A, the same method of 3B is implemented, then, by epoxy be hydrolyzed into glycol can with for example with above-mentioned steps 5A, 5B, 5C, the same method of 5D is implemented, then, oxidation cracking by glycol carry out to 24 ketone derive can with for example with above-mentioned steps 6A, the same method of 6C is implemented, can use Baeyer-Villiger oxidation (Baeyer-villiger oxidation) method by 24 ketone to deriving of 24 carboxylic acids or isopropyl esters, this method has been used normally used peracid in the organic chemistry, for example, can use and for example above-mentioned steps 3A, the same method of 3B is implemented.
In addition, above-mentioned any matrix can be carried out the oxidation cracking and is derivatized to 24 aldehyde or 24 carboxylic acids by two keys of 24 directly being carried out ozone oxidation.
In addition, as the steroid of carbonatoms more than 22 that generates from carbohydrate with fermentation method, can enumerate zymosterol, courage steroid-7,24-diene-3 β-alcohol, courage steroid-5,7,24-triolefin-3 β-alcohol, desmosterol, fucosterol, Episterol, ergot steroid-5,7,24 (28)-three enols, ergot steroid-5,7,22,24 (28)-tetraene alcohol, ergosterol etc.These compounds by for example with above-mentioned steps 4A, the method that 4B is same, comprise the three-dimensional step that makes up of 5 β that undertaken by the reduction saturation of 4 two keys, as required, carry out the oxidation of 3 hydroxyls and 5 two keys to 4 isomerized step by combination (I), (II) cut off 24 steps that become carboxyl or its ester derivative by the oxidation of side chain, (III) 7 steps that import oxygen functional group, can prepare above-mentioned general formula (8), (21a), (21b), (21c) or (21d) (in the formula, R1 represents the alkyl of hydrogen atom or carbonatoms 1～6) expression 3,7-dioxo-5 β-cholanic acid (8), Ursodeoxycholic Acid (UDCA) (21a), gallodesoxycholic acid (21b) or 3 Alpha-hydroxies-7-oxo-5 β-cholanic acid (21c), 7-hydroxyl-3-oxo-5 β-cholanic acid (21d) or these sour ester derivatives.
Embodiment
Below, specifically describe the present invention by embodiment, but scope of the present invention is not limited by embodiment.In addition, the structure of resultant is passed through 1H-NMR (300 or 400MHz, TMS/CDCl 3) determine.
[embodiment 1]
＜courage steroid-4,7, the preparation of 24-triolefin-3-ketone (compound 3) 〉
With 4.38g (11.47mmol) courage steroid-5,7,24-triolefin-3-alcohol (compound 2) and 11.24g (114.66mmol) pimelinketone are dissolved in the 44ml toluene, after at room temperature carrying out the several decompression degassing and nitrogen displacement repeatedly, at room temperature add 1.17g (5.74mmol) aluminum isopropylate, under the nitrogen atmosphere, stirred 2 hours at 112 ℃.With the reaction solution cool to room temperature, add 2.3ml water and also at room temperature stirred 1 hour after reaction finishes.The precipitation that filtration is separated out, concentrated filtrate separates purification with silica gel column chromatography, obtains 4.01g courage steroid-4,7,24-triolefin-3-ketone (compound 3).The yield that separates the compound 2 of purifying is 92%, and (δ ppm) is as follows for its NMR shift value.
δ：0.60(s，3H，18-H)，0.96(d，6.5Hz，3H，21-H)，1.18(s，3H，19-H)，1.61(s，3H，26-H)，1.69(s，3H，27-H)，2.22(m，1H)，2.30-2.40(m，3H)，2.63-2.72(m，1H，6-H)，3.10-3.20(m，1H，6-H)，5.09(m，1H，24-H)，5.18(m，1H，7-H)，5.80(s，1H，4-H)
[embodiment 2]
＜courage steroid-4,6, the preparation of 24-triolefin-3-ketone (compound 4) 〉
The courage steroid-4 that 3.49g (9.18mmol) is obtained with the method for embodiment 1,7,24-triolefin-3-ketone (compound 3) is dissolved in the 70ml methyl alcohol, after at room temperature carrying out the several decompression degassing and nitrogen displacement repeatedly, the 85% granular potassium hydroxide that adds 2.53g (38.40mmol) stirred 7 hours at 64 ℃ under the nitrogen atmosphere.With the reaction solution cool to room temperature, add 2.37g acetate and also at room temperature stirred 0.5 hour after reaction finishes.Then, under reduced pressure heat up in a steamer methyl alcohol, add entry, and use ethyl acetate extraction,, separate purification, obtain 3.13g courage steroid-4,7,24-triolefin-3-ketone (compound 4) with silica gel column chromatography with organic phase washing, dry, concentrated.The yield that separates the compound 3 of purifying is 90%, and (δ ppm) is as follows for its NMR shift value.
δ: 0.76 (s, 3H, 18-H), 0.95 (d, 6.5Hz, 3H, 21-H), 1.12 (s, 3H, 19-H), 1.61 (s, 3H, 26-H), 1.69 (s, 3H, 27-H), 2.19 (m, 1H), 2.39-2.65 (m, 2H), 5.09 (m, 1H, 24-H), 5.67 (s, 1H, 4-H), 6.12 (m, 2H, 6-H and 7-H)
[embodiment 3]
＜ergot steroid-4,6, the preparation of 24-triolefin-3-ketone 〉
With 0.20g (0.50mmol) ergot steroid-4,7,24-triolefin-3-ketone is dissolved in the 10ml methyl alcohol, at room temperature carries out repeatedly after the several decompression degassing and nitrogen replaces, the 85% granular potassium hydroxide that adds 0.10g (1.52mmol) stirred 12 hours at 65 ℃ under the nitrogen atmosphere.With the reaction solution cool to room temperature, add 0.18g acetate and also at room temperature stirred 0.5 hour after reaction finishes.Then, under reduced pressure heat up in a steamer methyl alcohol, add entry, and use ethyl acetate extraction,, separate purification, obtain 0.20g ergot steroid-4,6,24-triolefin-3-ketone with silica gel column chromatography with organic phase washing, dry, concentrated.Yield is 100%, and (δ ppm) is as follows for its NMR shift value.
δ：0.77(s，3H)，0.81(d，7.3Hz，3H)，0.83(d，7.3Hz，3H)，0.91(d，7.3Hz，3H)，1.01(d，7.3Hz，3H)，1.12(s，3H)，2.20(m，1H)，2.38-2.66(m，2H)，5.11-5.27(m，2H)，5.67(s，1H)，6.06-6.17(m，2H)
In addition, the reaction formula of present embodiment is as follows.
Figure A20058003063000661
[comparative example 1]
＜courage steroid-4,7, the preparation of 24-triolefin-3-ketone (compound 3) 〉
With 0.20g (0.5mmol) courage steroid-5,7,24-triolefin-3-alcohol (compound 2) and 0.26g (2.6mmol) pimelinketone are dissolved in the 2ml heptane, at room temperature add 0.02g (0.1mmol) aluminum isopropylate, and reflux is 4 hours under open system.After reaction finishes,, add entry and also at room temperature stirred 1 hour the reaction solution cool to room temperature.The precipitation that filtration is separated out, concentrated filtrate, the material after detect concentrating with HPLC, the yield of compound 3 is 85%.
[comparative example 2]
＜courage steroid-4,6, the preparation of 24-triolefin-3-ketone (compound 4) 〉
With the courage steroid-4,7 that 0.3g (0.8mmol) obtains with the method for embodiment 1,24-triolefin-3-ketone (compound 3) is dissolved in the 5.3ml methyl alcohol, adds the 85% granular potassium hydroxide of 0.09g (1.4mmol), and reflux is 4 hours under open system.With the reaction solution cool to room temperature, add 2.37g acetate and also at room temperature stirred 0.5 hour after reaction finishes.Then, under reduced pressure heat up in a steamer methyl alcohol, add entry, and use ethyl acetate extraction, with organic phase washing, dry, concentrate, detect material after concentrating with HPLC, the yield of compound 4 is 52%.
[embodiment 4-1]
＜step 3A:6,7:24, the preparation of 25-diepoxy courage steroid-4-alkene-3-ketone (compound 5) 〉
With 0.10g (0.26mmol) courage steroid-4,6,24-triolefin-3-ketone is dissolved in 0.3M peroxybenzoic acid/ethyl acetate solution of 3.5ml (1mmol), stirs 8 hours down at 45 ℃.After reaction finishes, in reaction solution, add 10% sodium sulfite aqueous solution,, use ethyl acetate extraction remaining peroxide breakdown.Then, with the saturated potassium hydrogen carbonate aqueous solution organic phase is washed, dry, concentrate, it is thick 6 to obtain 0.138g, 7:24,25-diepoxy courage steroid-4-alkene-3-ketone.Yield is 70%, and (δ ppm) is as follows for its NMR shift value.
δ：0.75(s，3H，18-H)，0.95(d，5.7Hz，3H，21-H)，1.10(s，3H，19-H)，1.27(s，3H，26-H)，1.30(s，3H，27-H)，2.4-2.6(m，2H)，2.69(t，5.5Hz，1H，24-H)，3.3-3.4(m，1H，7-H)，3.47(d，3.3Hz，1H，6-H)，6.12(s，1H，4-H)
[embodiment 4-2]
＜step 3A:6,7:24, the preparation of 25-diepoxy courage steroid-4-alkene-3-ketone (compound 5) 〉
With 1.00g (2.63mmol) courage steroid-4,6,24-triolefin-3-ketone is dissolved in the 11.7ml n-butyl acetate, and adding 4ml water, at 2-methyl peroxybenzoic acid/n-butyl acetate solution (being designated hereinafter simply as peracid solutions) of the 1.04M that in this mixed solution, drips 2.53ml (2.63mmol) under 78 ℃, stirred 1 hour down at 78 ℃.Then, separatory is removed water, washs with saturated sodium bicarbonate water, wash again, add 4ml water, again in mixed solution (※ 1) 78 ℃ of peracid solutions that add 0.50ml (0.53mmol) down, 78 ℃ stir 0.5 hour down after, the peracid solutions that adds 0.50ml (0.53mmol) again, stirred 0.5 hour down at 78 ℃, separatory is removed water, washs with saturated sodium bicarbonate water, wash again, add 4ml water.For this mixed solution, repeat 2 operations same with ※ 1.In addition, 78 ℃ of peracid solutions that add 0.50ml (0.53mmol) down, after stirring 0.5 hour under 78 ℃, again 78 ℃ of peracid solutions that add 0.50ml (0.53mmol) down, stirring is after 0.5 hour down at 78 ℃, and cool to room temperature adds S-WAT in reaction solution, with remaining peroxide breakdown, use ethyl acetate extraction.Then, with saturated sodium bicarbonate aqueous solution organic phase is washed, dry, concentrate, it is thick 6 to obtain 1.33g, 7:24,25-diepoxy courage steroid-4-alkene-3-ketone.Yield is 82%.
Thick 6 to what obtain, 7:24,25-diepoxy courage steroid-4-alkene-3-ketone carries out thin-layer chromatography, separates 6 α, 7 α bodies and 6 β, 7 β bodies, (δ ppm) is as follows for its NMR shift value.
6 α, 7 α; 24,25-diepoxy courage steroid-4-alkene-3-ketone
δ: 0.75 (s, 3H, 18-H), 0.94 (d, 6.8Hz, 3H, 21-H), 1.09 (s, 3H, 19-H), 1.27 with 1.31 (s, 6H, 26-H and 27-H), and 2.42-2.60 (m, 2H), 2.69 (t, 6.0Hz, 1H, 24-H), 3.35 (d, 3.6Hz, 1H, 7-H), 3.46 (d, 4.0Hz, 1H, 6-H), 6.11 (s, 1H, 4-H)
6 β, 7 β; 24,25-diepoxy courage steroid-4-alkene-3-ketone
δ: 0.75 (s, 3H, 18-H), 0.95 (d, 6.5Hz, 3H, 21-H), 1.21 (s, 3H, 19-H), 1.27 and 1.31 (s, 6H, 26-H and 27-H), 2.36-2.64 (m, 2H), 2.69 (t, 5.5Hz, 1H, 24-H), 3.37 (s, 2H, 6-H and 7-H), 6.15 (s, 1H, 4-H)
[embodiment 5-1]
＜step 4A:5 β-24, the preparation of 25-epoxy courage steroid-3-ketone-7-alcohol (compound 6) 〉
With 0.128g by the foregoing description 4-1 obtain 6,7:24,25-diepoxy courage steroid-4-alkene-3-ketone is dissolved in the 1.8ml ethyl acetate, to the 10% year palladium carbon that wherein adds 0.5ml triethylamine and 7mg, under the normal pressure hydrogen atmosphere stirring at room 15 hours.Reaction finishes the after-filtration catalyzer, and filtrate is concentrated, and makes this concentrated solution by short silica gel column chromatography, concentrates then, obtains thick 5 β-24 of 0.077g, 25-epoxy courage steroid-3-ketone-7-alcohol.Yield is 87%, and (δ ppm) is as follows for its NMR shift value.
δ：0.70(s，3H，18-H)，0.95(d，5.5Hz，3H，21-H)，1.00(s，3H，19-H)，1.27(s，3H，26-H)，1.30(s，3H，27-H)，2.15-2.25(m，2H)，2.3-2.5(m，1H)，2.69(t，5.5Hz，1H，24-H)，3.40(t，13.3Hz，1H，4-H)，3.92(m，1H，7-H)
To thick 5 β-24 that obtain, 25-epoxy courage steroid-3-ketone-7-alcohol carries out thin-layer chromatography, separates 7 α bodies and 7 β body and reaction intermediates, and (δ ppm) is as follows for its NMR shift value.
5 β-24,25-epoxy courage steroid-3-ketone-7 α-alcohol
δ: 0.71 (s, 3H, 18-H), 0.96 (d, 6.0Hz, 3H, 21-H), 1.01 (s, 3H, 19-H), 1.27 with 1.31 (s, 6H, 26-H and 27-H), and 2.12-2.23 (m, 2H), 2.41 (dt, 14Hz and 4.8Hz, 1H), 2.69 (t, 6.0Hz, 1H, 24-H), 3.39 (t, 13.2Hz, 1H, 4-H), 3.93 (m, 1H, 7-H)
5 β-24,25-epoxy courage steroid-3-ketone-7 β-alcohol
δ: 0.73 (s, 3H, 18-H), 0.96 (d, 6.6Hz, 3H, 21-H), 1.06 (s, 3H, 19-H), 1.27 and 1.31 (s, 6H, 26-H and 27-H), 2.15-2.35 (m, 3H), 2.52 (t, 11.0Hz, 1H), 2.69 (t, 6.1Hz, 1H, 24-H), 3.56-3.68 (m, 1H, 7-H)
24,25-epoxy courage steroid-4-alkene-3-ketone-7 α-alcohol
δ: 0.73 (s, 3H, 18-H), 0.94 (d, 6.8Hz, 3H, 21-H), 1.19 (s, 3H, 19-H), 1.27 with 1.31 (s, 6H, 26-H and 27-H), and 2.33-2.46 (m, 3H), 2.60-2.64 (m, 1H), 2.69 (t, 6.4Hz, 1H, 24-H), 3.97 (m, 1H, 7-H), 5.81 (d, 1.6Hz, 1H, 4-H)
24,25-epoxy courage steroid-4-alkene-3-ketone-7 β-alcohol
δ: 0.74 (s, 3H, 18-H), 0.95 (d, 6.8Hz, 3H, 21-H), 1.21 (s, 3H, 19-H), 1.27 and 1.31 (s, 6H, 26-H and 27-H), 2.31-2.56 (m, 4H), 2.69 (t, 6.0Hz, 1H, 24-H), 3.42-3.50 (m, 1H, 7-H), 5.76 (d, 1.2Hz, 1H, 4-H)
[embodiment 5-2]
＜step 4A:5 β-24, the preparation of 25-epoxy courage steroid-3-ketone-7-alcohol (compound 6) 〉
With 2.6mg 5% carry the palladium carbon suspension in 1060 μ L methyl alcohol, add 25 μ L (0.165mmol) Tetramethyl Ethylene Diamines, under nitrogen, stirred 3 hours at 50 ℃.Then, cool to room temperature adds 206 μ L water, will be replaced as normal pressure hydrogen in the system, at room temperature stirs 1 hour.Then, the catalyst suspension of pre-treatment is cooled to 5 ℃, under hydrogen atmosphere, drop into 100mg (0.242mmol) with silicagel column purification the foregoing description 1-2 obtain thick 6,7:24,310 μ L n-butyl acetate solution of 25-diepoxy courage steroid-4-alkene-3-ketone and 424 μ L methyl alcohol, under the normal pressure hydrogen atmosphere, stirred 49 hours down at 5 ℃.Reaction finishes the after-filtration catalyzer, and filtrate is concentrated, and makes this concentrated solution by short silica gel column chromatography, concentrates then, obtains thick 5 β-24 of 115mg, 25-epoxy courage steroid-3-ketone-7-alcohol.Yield is 96%.
[embodiment 6-1]
＜step 5A:5 β-courage steroid-3-ketone-7,24, the preparation of 25-triol (compound 7) 〉
Thick 5 β-24 that 0.077g (0.19mmol) the foregoing description 5-1 is obtained, 25-epoxy courage steroid-3-ketone-7-alcohol is adsorbed on the silicagel column, with hexane-ethyl acetate mixed solution wash-out, obtains 5 β-courage steroid-3-ketone-7,24 of 0.080g, the 25-triol.Yield is 100%, and (δ ppm) is as follows for its NMR shift value.
δ: 0.71 (s, 3H, 18-H), 0.95 and 0.96 (d, 6.8Hz, 3H, 21-H), 1.01 (s, 3H, 19-H), 1.17 with 1.21 (s, 6H, 26-H and 27-H), and 2.15-2.23 (m, 2H), 2.35-2.45 (m, 1H), 3.27-3.33 (m, 1H, 24-H), 3.39 (t, 15.6Hz, 1H, 4-H), 3.93 (m, 1H, 7-H)
[embodiment 6-2]
＜step 5A:5 β-courage steroid-3-ketone-7,24, the preparation of 25-triol (compound 7) 〉
With 5 β-24 that 145mg (0.35mmol) the foregoing description 5-2 obtains, 25-epoxy courage steroid-3-ketone-7-alcohol is dissolved in the mixed solution of 1ml acetonitrile and 1ml water, adds 73mg (0.35mmol) citric acid monohydrate compound, at room temperature stirs 9 hours.Reaction finishes the back and adds in the sodium bicarbonate and citric acid, under reduced pressure distillates acetonitrile, uses ethyl acetate extraction again.This extraction liquid is concentrated, obtain thick 5 β of 150mg-courage steroid-3-ketone-7,24, the 25-triol.Yield is 98%.
[embodiment 7]
＜step 6A:3, the preparation of 7-dioxo-5 β-cholanic acid (compound 8) 〉
5 β-courage steroid-3-ketone-7 with 93mg (0.22mmol), 24, the 25-triol is dissolved in 1.5ml acetonitrile, the 1.1ml water, at room temperature adds 60% Losantin of 0.17g (0.44mmol), adds 0.12g acetate and also at room temperature stirred 40 minutes in this mixture.After reaction finishes, add 10% sodium sulfite aqueous solution excessive oxygenant is decomposed, adding concentrated hydrochloric acid adjusting pH is 1, separates purification with silica gel column chromatography behind the concentrating under reduced pressure, obtains 3 of 75mg, 7-two-oxo-5 β-cholanic acid.Yield is 92%, and (δ ppm) is as follows for its NMR shift value.
δ: 0.72 (s, 3H, 18-H), 0.95 (d, 6.3Hz, 3H, 21-H), 1.30 (s, 3H, 19-H), 2.50 (t, 10.7Hz, 1H), 2.88 (dd, 5.1Hz and 14.2Hz, 1H)
[embodiment 8]
＜step 5B:6,7-epoxy courage steroid-4-alkene-3-ketone-24, the preparation of 25-glycol (compound 9) 〉
Make 0.120g according to thick 6 with the same method synthetic of embodiment 4-1,7:24,25-diepoxy courage steroid-4-alkene-3-ketone is adsorbed on the silicagel column, with hexane-ethyl acetate mixed solution wash-out, it is thick 6 to obtain 0.080g, 7-epoxy courage steroid-4-alkene-3-ketone-24,25-glycol.Yield is 80%, and (δ ppm) is as follows for its NMR shift value.
δ: 0.75 (s, 3H, 18-H), 0.95 and 0.96 (d, 6.8Hz, 3H, 21-H), 1.10 (s, 3H, 19-H), 1.18 (s, 3H, 26-H), 1.23 (s, 3H, 27-H), 2.4-2.6 (m, 2H), 3.25-3.31 (m, 1H, 24-H), 3.33-3.38 (m, 1H, 7-H), 3.46 (d, 3.7Hz, 1H, 6-H), 6.12 (s, 1H, 4-H)
[embodiment 9]
＜step 4B:5 β-courage steroid-3-ketone-7,24, the preparation of 25-triol (compound 6) 〉
With 6 after with the same method of embodiment 5-1 0.075g being purified, 7-epoxy courage steroid-4-alkene-3-ketone-24, the reduction of 25-glycol, this purification be with use with the same method of the foregoing description 5 obtain thick 6,7-epoxy courage steroid-4-alkene-3-ketone-24,25-glycol carry out silicagel column and purify, purify by silica gel column chromatography again, obtain 5 β-courage steroid-3-ketone-7 α of 0.068g, 24, the 25-triol.Yield is 90%.In addition, confirmed that the NMR data are identical with embodiment 6-1.
[embodiment 10]
(step 3B:24,25-epoxy courage steroid-4, the preparation of 6-diene-3-ketone (compound 10) 〉
With 0.10g (0.27mmol) courage steroid-4,6,24-triolefin-3-ketone is dissolved in the 2ml ethyl acetate, adds monoperphthalic acid/ethyl acetate solution of the 0.42M of 0.76ml (0.32mmol), at room temperature stirs 3 hours.After reaction finishes, in reaction solution, add 10% sodium sulfite aqueous solution,, use ethyl acetate extraction remaining peroxide breakdown.Then, with the saturated potassium hydrogen carbonate aqueous solution with the organic phase washing, dry, concentrate, it is thick 24 to obtain 0.11g, 25-epoxy courage steroid-4,6-diene-3-ketone.Yield is 100%, and (δ ppm) is as follows for its NMR shift value.
δ: 0.77 (s, 3H, 18-H), 0.95 (d, 6.4Hz, 3H, 21-H), 1.11 (s, 3H, 19-H), 1.27 (s, 3H, 26-H), 1.31 (s, 3H, 27-H), 2.15-2.23 (m, 1H), 2.38-2.65 (m, 2H, 2-H), 2.69 (t, 5.5Hz, 1H, 24-H), 5.67 (s, 1H, 4-H), 6.07-6.16 (m, 2H, 6-H and 7-H)
[embodiment 11]
＜step 5C: courage steroid-4,6-diene-3-ketone-24, the preparation of 25-glycol (compound 11) 〉
Make 0.110g thick 24 based on embodiment 7 synthetic, 25-epoxy courage steroid-4,6-diene-3-ketone (compound 10) is adsorbed on the silicagel column, with hexane-ethyl acetate mixed solution wash-out, obtains the courage steroid-4 of 0.070g, 6-diene-3-ketone-24,25-glycol.Yield is 61%, and (δ ppm) is as follows for its NMR shift value.
δ: 0.76 and 0.77 (s, 3H, 18-H), 0.94 and 0.95 (d, 6.6Hz, 3H, 21-H), 1.11 (s, 3H, 19-H), 1.17 (s, 3H, 26-H), 1.21 (s, 3H, 27-H), and 2.37-2.64 (m, 2H), 3.25-3.37 (m, 1H, 24-H), 5.67 (s, 1H, 4-H), 6.05-6.16 (m, 2H, 6-H and 7-H)
[embodiment 12]
＜step 3C:6,7-epoxy courage steroid-4-alkene-3-ketone-24, the preparation of 25-glycol (compound 9) 〉
With with the same method of embodiment 4-2 with 66mg (0.159mmol) based on embodiment 11 synthetic courage steroids-4,6-diene-3-ketone-24,25-glycol (compound 11) epoxidation, purify by silica gel column chromatography again, obtain 6 of 48mg, 7-epoxy courage steroid-4-alkene-3-ketone-24,25-glycol.Yield is 70%.In addition, confirmed that the NMR data are identical with embodiment 8.
[embodiment 13]
＜step 6B:5 β-24,25-epoxy courage steroid-3, the preparation of 7-diketone (compound 12) 〉
With 667mg based on thick 5 β-24 of embodiment 5-2 synthetic, 25-epoxy courage steroid-3-ketone-7-alcohol (compound 6) is dissolved in 5.4ml acetonitrile, the 2.7ml water, the NaBr that adds 1.21ml acetate and 31mg again, at 60% Losantin that in this mixture, adds 0.36g (1.51mmol) under 0 ℃, stirred 23 hours down at 0 ℃.After reaction finishes, add S-WAT excessive oxygenant is decomposed, use ethyl acetate extraction, with the saturated sodium bicarbonate aqueous solution washing, then wash, dry back concentrating under reduced pressure obtains thick 5 β-24 of 576mg, 25-epoxy courage steroid-3,7-diketone.Yield is 96%, and (δ ppm) is as follows for its NMR shift value.
δ: 0.70 (s, 3H, 18-H), 0.95 (d, 6.4Hz, 3H, 21-H), 1.27 and 1.31 (s, 6H, 26-H and 27-H), 1.31 (s, 3H, 19-H), 2.50 (t, 11.2Hz, 1H), 2.69 (t, 6.4Hz, 1H, 24-H), 2.89 (dd, 5.6Hz and 12.8Hz, 1H)
[embodiment 14]
＜step 5D:5 β-courage steroid-3,7-diketone-24, the preparation of 25-glycol (compound 13) 〉
With thick 5 β-24 that 419mg embodiment 13 obtained with the same method of embodiment 6-2,25-epoxy courage steroid-3,7-diketone (compound 12) is hydrolyzed, and obtains thick 5 β of 410mg-courage steroid-3,7-diketone-24,25-glycol.Yield is 97%, and (δ ppm) is as follows for its NMR shift value.
δ: 0.70 and 0.71 (s, 3H, 18-H), 0.94 and 0.95 (d, 6.0Hz, 3H, 21-H), 1.16 and 1.21 (s, 6H, 26-H and 27-H), 1.31 (s, 3H, 19-H), 2.51 (t, 11.6Hz, 1H), 2.89 (dd, 5.6Hz and 12.8Hz, 1H), 3.27-3.35 (m, 1H, 24-H)
[embodiment 15]
＜step 6C:3, the preparation of 7-dioxo-5 β-cholanic acid (compound 8) 〉
Thick 5 β-courage steroid-3 that 390mg embodiment 14 is obtained, 7-diketone-24,25-glycol (compound 13) is dissolved in 6ml acetonitrile, the 2.7ml water, add 0.17ml acetate again, at 60% Losantin that in this mixture, adds 294mg (1.23mmol) under 10 ℃, stirred 26.5 hours down at 10 ℃.After reaction finishes, add the oxygenant that S-WAT will be excessive and decompose, add concentrated hydrochloric acid and regulate pH＜1, use ethyl acetate extraction, washing, drying, concentrated obtain the thick 3 of 381mg, 7-dioxo-5 β-cholanic acid.Yield is 84%, in addition, has confirmed that the NMR data are identical with embodiment 7.
[embodiment 16]
＜step 7:6,7:24, the preparation of 25-diepoxy courage steroid-4-alkene-3-ketone (compound 5) 〉
With 547mg (1.44mmol) courage steroid-4,6,24-triolefin-3-ketone is dissolved in the 10ml formic acid under 10 ℃, adds 520 μ L t-butyl hypochlorite salt, stirs 30 minutes down at 10 ℃.Add entry after reaction finishes, use ethyl acetate extraction, after washing, the saturated sodium bicarbonate aqueous solution washing, drying, concentrated, obtain the thick 7 of 870mg, 24-two chloro-courage steroids-4-alkene-3-ketone-6,25-glycol dicarboxylic acid esters (compound 15).Yield is about 70%, and (δ ppm) is as follows for its NMR shift value.
δ: 0.77 (s, 3H, 18-H), 0.93 and 0.95 (d, 4.9Hz and 6.5Hz, 3H; 21-H), 1.28 (s, 3H, 19-H), 1.60 (s, 6H; 26-H and 27-H), 2.38-2.57 (m, 2H), 4.14 (t, 3.0Hz, 1H); 4.25 (t, 12.0Hz, 1H), 5.55 (d, 1.9Hz, 1H; 6-H), 6.04 (s, 1H, 4-H), 8.00 (s; 1H, formyl radical), 8.05 (s, 1H, formyl radicals)
Then, with above-mentioned obtain thick 7 of 870mg, 24-two chloro-courage steroids-4-alkene-3-ketone-6,25-glycol dicarboxylic acid esters (compound 15) is dissolved in the 15ml methyl alcohol, adds the KHCO of 300mg 3(3mmol), at room temperature stirred 8 hours, carry out the cut-out of ester.In addition, the K that adds 694mg 2CO 3(5mmol), at room temperature stirred 24 hours, carry out pass ring to the epoxy of intermediate chloropharin.After reaction finishes, add 1ml acetate, concentrate methyl alcohol, add entry and use ethyl acetate extraction, dry, concentrate after, with the silica gel column chromatography purification, obtain the thick 6 of 341mg, 7:24,25-diepoxy courage steroid-4-alkene-3-ketone.The total recovery of 2 steps is about 57%.
In addition, what obtain is thick 6,7:24, and 25-diepoxy courage steroid-4-alkene-3-ketone only is 6 β, 7 β epoxies.
[embodiment 17]
＜phenylformic acid-6,7-dihydroxyl-3, the preparation of 7-dimethyl monooctyl ester 〉
The 1-benzoyl geraniol of 0.50g (1.92mmol) is dissolved in the 6ml chloroform, adds 0.99g (5.76mmol) metachloroperbenzoic acid, at room temperature stirred 1 hour.After reaction finishes, in reaction solution, add 10% sodium sulfite aqueous solution,, use chloroform extraction remaining peroxide breakdown.Then, obtain 0.49g crude benzol formic acid-5-(3,3-dimethyl peroxidation ketone group)-3-methyl pentyl ester with saturated potassium hydrogen carbonate solution washing, drying, concentrated.Yield is 92%, and (δ ppm) is as follows for its NMR shift value.
δ：1.00(d，7.7Hz，3H)，1.28(s，3H)，1.30(s，3H)，1.4-1.9(m，H)，2.72(t，6.6Hz，1H)，4.37(m，2H)，7.45(m，2H)，7.57(m，1H)，8.04(m，2H)
Then, crude benzol formic acid-5-(3,3-dimethyl peroxidation ketone group)-3-methyl pentyl ester that 0.10g (0.36mmol) is obtained is dissolved in the 2ml ethyl acetate, adds 22mg water, 17mg acetate and 0.20g silica gel, stirs 24 hours down at 40 ℃.Reaction finishes after-filtration silica gel, and filtrate is concentrated, and obtains 0.10g crude benzol formic acid-6,7-dihydroxyl-3,7-dimethyl monooctyl ester.Transformation efficiency is 100%, and yield is 94%, does not detect object by product in addition.(δ ppm) is as follows for its NMR shift value.
δ：0.99(t，5.3Hz，3H)，1.16(s，3H)，1.21(s，3H)，1.2-1.95(m，7H)，2.14-2.25(m，1H)，3.32(m，1H)，4.3-4.45(m，2H)，7.44(t，7.7Hz，2H)，7.54(m，1H)，8.04(d，8.2Hz，2H)
In addition, the reaction formula of present embodiment is as follows.
Figure A20058003063000741
Industrial applicibility
According to the present invention, use the courage steroid-5,7 at one of 5 and 24 sterols with two keys, 24-three Alkene-3 β-alcohol is raw material, can be effectively and prepare at an easy rate 3,7-dioxo-5 β-cholestanic and ester spreads out Biology, this material are the useful courage steroids as the synthetic intermediate of various steroid pharmaceuticals-4, the weight of 6,24-triolefin-3-ketone or the various steroid medicine such as ursodesoxycholic acid or chenodesoxycholic acid The synthetic intermediate of wanting. Can seek stable supplying by establishing cheap chemical synthesis, to enlarging The contribution of purposes is big.

Claims (49)

1. following general formula (8), (21a), (21b), (21c) or (21d)
Figure A2005800306300002C1
(in the formula, R 1The alkyl of expression hydrogen atom or carbonatoms 1～6) 3 of expression, the preparation method of 7-dioxo-5 β-cholanic acid (8), Ursodeoxycholic Acid (UDCA) (21a), gallodesoxycholic acid (21b) or 3 Alpha-hydroxies-7-oxo-5 β-cholanic acid (21c), 7-hydroxyl-3-oxo-5 β-cholanic acid (21d) or these sour ester derivatives, it is characterized in that, with the steroid of carbonatoms more than 22 that generate by carbohydrate with fermentation method as raw material, and comprising the step of carrying out the three-dimensional structure of 5 β, the three-dimensional structure by the reduction saturation of 4 two keys of described 5 β undertaken.
2. following general formula (8), (21a), (21b), (21c) or (21d)
Figure A2005800306300003C1
(in the formula, R 1The alkyl of expression hydrogen atom or carbonatoms 1～6) 3 of expression, the preparation method of 7-dioxo-5 β-cholanic acid (8), Ursodeoxycholic Acid (UDCA) (21a), gallodesoxycholic acid (21b) or 3 Alpha-hydroxies-7-oxo-5 β-cholanic acid (21c), 7-hydroxyl-3-oxo-5 β-cholanic acid (21d) or these sour ester derivatives, it is characterized in that, or (A8) at following general formula (A1), (A2), (A3), (A4), (A5), (A6), (A7)
Figure A2005800306300003C2
Figure A2005800306300004C1
(in the formula, A 1Expression hydrogen atom or sec.-propyl, A 2, A 3Independent separately, A 1Represent methyl during for hydrogen atom, A 1Represent hydrogen atom or methyl during for sec.-propyl, B 1, B 2And B 3Independent separately, expression hydroxyl or protected hydroxyl, n represents 0 or 1 integer) in the steroid of expression, carry out that 5 β are three-dimensional to be made up, the three-dimensional structure by the reduction saturation of 4 two keys of described 5 β undertaken.
3. the described following general formula of claim 2 (8), (21a), (21b), (21c) or (21d)
Figure A2005800306300004C2
(in the formula, R 1The alkyl of expression hydrogen atom or carbonatoms 1～6) 3 of expression, the preparation method of 7-dioxo-5 β-cholanic acid (8), Ursodeoxycholic Acid (UDCA) (21a), gallodesoxycholic acid (21b) or 3 Alpha-hydroxies-7-oxo-5 β-cholanic acid (21c), 7-hydroxyl-3-oxo-5 β-cholanic acid (21d) or these sour ester derivatives, it is characterized in that following general formula (A1), (A2), (A3), (A4), (A5), (A6), (A7) or (A8)
Figure A2005800306300005C1
(in the formula, A 1Expression hydrogen atom or sec.-propyl, A 2, A 3Independent separately, A 1Represent methyl during for hydrogen atom, A 1Represent hydrogen atom or methyl during for sec.-propyl, B 1, B 2And B 3Independent separately, expression hydroxyl or protected hydroxyl, n represents 0 or 1 integer) be by following general formula (1)
Figure A2005800306300005C2
(in the formula, A 1Expression hydrogen atom or sec.-propyl, A 2, A 3Independent separately, A 1Represent methyl during for hydrogen atom, A 1Represent hydrogen atom or methyl during for sec.-propyl, C I～C IIBetween key be singly-bound or two key) expression sterol compound deutero-material.
4. following general formula (8), (21a), (21b), (21c) or (21d)
Figure A2005800306300006C1
(in the formula, R 1The alkyl of expression hydrogen atom or carbonatoms 1～6) 3 of expression, the preparation method of 7-dioxo-5 β-cholanic acid (8), Ursodeoxycholic Acid (UDCA) (21a), gallodesoxycholic acid (21b) or 3 Alpha-hydroxies-7-oxo-5 β-cholanic acid (21c), 7-hydroxyl-3-oxo-5 β-cholanic acid (21d) or these sour ester derivatives, wherein, with following general formula (1)
Figure A2005800306300006C2
(in the formula, A 1Expression hydrogen atom or sec.-propyl, A 2, A 3Independent separately, A 1Represent methyl during for hydrogen atom, A 1Represent hydrogen atom or methyl during for sec.-propyl, C I～C IIBetween key be singly-bound or two key) sterol compound of expression is raw material, and comprise the steps:
(I) carry out the oxidation of 3 hydroxyls and 5 two keys to 4 isomerized step; With
(II) cut off 24 steps that change into carboxyl or its ester derivative by the oxidation of side chain; With
(III) 7 steps that import oxygen functional group; And
(IV) carry out the three-dimensional step that makes up of 5 β by the reduction saturation of 4 two keys.
5. the described following general formula of claim 4 (8), (21a), (21b), (21c) or (21d)
Figure A2005800306300007C1
(in the formula, R 1The alkyl of expression hydrogen atom or carbonatoms 1～6) 3 of expression, the preparation method of 7-dioxo-5 β-cholanic acid (8), Ursodeoxycholic Acid (UDCA) (20a), gallodesoxycholic acid (20b) or 3 Alpha-hydroxies-7-oxo-5 β-cholanic acid (20c), 7-hydroxyl-3-oxo-5 β-cholanic acid (20d) or these sour ester derivatives, wherein, following general formula (1)
Figure A2005800306300007C2
(in the formula, A 1Expression hydrogen atom or sec.-propyl, A 2, A 3Independent separately, A 1Represent methyl during for hydrogen atom, A 1Represent hydrogen atom or methyl during for sec.-propyl, C I～C IIBetween key be singly-bound or two key) expression sterol compound be courage steroid-5,7,24-triolefin-3 β-alcohol or ergot steroid-5,7,24 (28)-triolefins-3 β-alcohol, desmosterol or fucosterol, ergot steroid-5,24 (28)-diene-3 β-alcohol.
6. the described following general formula of claim 4 (8), (21a), (21b), (21c) or (21d)
Figure A2005800306300008C1
(in the formula, R 1The alkyl of expression hydrogen atom or carbonatoms 1～6) 3 of expression, the preparation method of 7-dioxo-5 β-cholanic acid (8), Ursodeoxycholic Acid (UDCA) (21a), gallodesoxycholic acid (21b) or 3 Alpha-hydroxies-7-oxo-5 β-cholanic acid (21c), 7-hydroxyl-3-oxo-5 β-cholanic acid (21d) or these sour ester derivatives, wherein, following general formula (1)
(in the formula, A 1Expression hydrogen atom or sec.-propyl, A 2, A 3Independent separately, A 1Represent methyl during for hydrogen atom, A 1Represent hydrogen atom or methyl during for sec.-propyl, C I～C IIBetween key be singly-bound or two key) expression sterol compound be courage steroid-5,7,24-triolefin-3 β-alcohol.
7. following formula (4)
The courage steroid-4,6 of expression, the preparation method of 24-triolefin-3-ketone is characterized in that, with following formula (2)
Figure A2005800306300009C1
The courage steroid-5,7 of expression, 24-triolefin-3 β-pure oxidation changes into following formula (3)
The courage steroid-4,7 of expression, 24-triolefin-3-ketone then carries out isomerization.
8. the described courage steroid-4,6 of claim 7, the preparation method of 24-triolefin-3-ketone is characterized in that, carries out oxidizing reaction in the presence of ketone compound and metal alkoxide.
9. the described courage steroid-4,6 of claim 8, the preparation method of 24-triolefin-3-ketone is characterized in that, carries out oxidizing reaction under the situation of isolation from oxygen.
10. the described courage steroid-4,6 of claim 8, the preparation method of 24-triolefin-3-ketone is characterized in that, the ketone compound general formula R 2(C=O) R 3(in the formula, R 2And R 3Chain or the cyclic alkyl of representing carbonatoms 1～10 respectively independently also can R 2And R 3Mutually combine and form the ring texture of carbonatoms 3～8) expression.
11. the described courage steroid-4,6 of claim 7, the preparation method of 24-triolefin-3-ketone is characterized in that, carries out isomerization reaction in the presence of basic cpd.
12. the described courage steroid-4,6 of claim 11, the preparation method of 24-triolefin-3-ketone is characterized in that, basic cpd is oxyhydroxide, carbonate or the alkoxide of basic metal or alkaline-earth metal.
13. the described courage steroid-4,6 of claim 11, the preparation method of 24-triolefin-3-ketone is characterized in that, carries out isomerization reaction under the situation of isolation from oxygen.
14. following formula (3)
Figure A2005800306300009C3
The courage steroid-4,7 of expression, 24-triolefin-3-ketone.
15. a 3-oxo-4, the preparation method of 7-diene steroid is characterized in that, as with following general formula (2a), (2b), (2c), (2d), (2e)
Figure A2005800306300010C1
(in the formula, R 4～R 8Independent separately; expression hydrogen atom, protected hydroxyl or halogen atom; perhaps can be by alkyl, alkenyl or the alkynyl of the carbonatoms 1～10 of carbonyl, ether, protected hydroxyl, halogen atom or carboxyl substituted) the 3-hydroxyl-5 of expression, 7-diene steroid is oxidized to following general formula (3a), (3b), (3c), (3d), (3e)
Figure A2005800306300010C2
(in the formula, R 4～R 8Independent separately; expression hydrogen atom, protected hydroxyl or halogen atom; perhaps can be by alkyl, alkenyl or the alkynyl of the carbonatoms 1～10 of carbonyl, ether, protected hydroxyl, halogen atom or carboxyl substituted) method of the compound of expression is to carry out under the situation of isolation from oxygen and in the presence of ketone compound and metal alkoxide.
16. a 3-oxo-4, the preparation method of 6-diene steroid is characterized in that, is catalyzer with alkali, respectively with following general formula (3a), (3b), (3c), (3d), (3e)
Figure A2005800306300011C1
(in the formula, R 4～R 8Independent separately; expression hydrogen atom, hydroxyl, protected hydroxyl or halogen atom; perhaps can be by alkyl, alkenyl or the alkynyl of the carbonatoms 1～10 of carbonyl, ether, hydroxyl, protected hydroxyl, halogen atom or carboxyl substituted) the 3-oxo-4 of expression, 7-diene steroid is isomerizated into following formula (4a), (4b), (4c), (4d), (4e)
Figure A2005800306300011C2
(in the formula, R 4～R 8Independent separately, expression hydrogen atom, hydroxyl, protected hydroxyl or halogen atom perhaps can be by alkyl, alkenyl or the alkynyls of the carbonatoms 1～10 of carbonyl, ether, hydroxyl, protected hydroxyl, halogen atom or carboxyl substituted) compound of expression.
17. following general formula (8)
Figure A2005800306300012C1
(in the formula, R 1The alkyl of expression hydrogen atom or carbonatoms 1～6) 3 of expression, the preparation method of 7-dioxo-5 β-cholanic acid or its ester derivative is characterized in that, with following formula (4)
Figure A2005800306300012C2
The courage steroid-4,6 of expression, 24-triolefin-3-ketone epoxy changes into following formula (5)
Figure A2005800306300012C3
6 of expression, 7:24,25-diepoxy courage steroid-4-alkene-3-ketone then carries out hydrogenation, changes into following formula (6)
Figure A2005800306300012C4
5 β-24 of expression, 25-epoxy courage steroid-3-ketone-7-alcohol is hydrolyzed again, changes into following formula (7)
Figure A2005800306300012C5
5 β-courage steroid-3-the ketone-7,24 of expression, the 25-triol carries out oxidation again, according to circumstances carries out esterification again.
18. following general formula (8)
Figure A2005800306300012C6
(in the formula, R 1The alkyl of expression hydrogen atom or carbonatoms 1～6) 3 of expression, the preparation method of 7-dioxo-5 β-cholanic acid or its ester derivative is characterized in that, with following formula (4)
The courage steroid-4,6 of expression, 24-triolefin-3-ketone epoxy changes into following formula (5)
Figure A2005800306300013C2
6 of expression, 7:24,25-diepoxy courage steroid-4-alkene-3-ketone then is hydrolyzed, and changes into following formula (9)
Figure A2005800306300013C3
6 of expression, 7-epoxy courage steroid-4-alkene-3-ketone-24, the 25-glycol carries out hydrogenation again, changes into following formula (7)
Figure A2005800306300013C4
5 β-courage steroid-3-the ketone-7,24 of expression, the 25-triol carries out oxidation again, according to circumstances carries out esterification again.
19. following general formula (8)
Figure A2005800306300013C5
(in the formula, R 1The alkyl of expression hydrogen atom or carbonatoms 1～6) 3 of expression, the preparation method of 7-dioxo-5 β-cholanic acid or its ester derivative is characterized in that, with following formula (4)
Figure A2005800306300013C6
The courage steroid-4,6 of expression, 24-triolefin-3-ketone epoxy changes into following formula (10)
Figure A2005800306300013C7
24 of expression, 25-epoxy courage steroid-4,6-diene-3-ketone then is hydrolyzed, and changes into following formula (11)
Figure A2005800306300014C1
The courage steroid-4 of expression, 6-diene-3-ketone-24, the 25-glycol then carries out epoxidation, changes into following formula (9)
Figure A2005800306300014C2
6 of expression, 7-epoxy courage steroid-4-alkene-3-ketone-24, the 25-glycol carries out hydrogenation again, changes into following formula (7)
Figure A2005800306300014C3
5 β-courage steroid-3-the ketone-7,24 of expression, the 25-triol carries out oxidation again, according to circumstances carries out esterification again.
20. following general formula (8)
(in the formula, R 1The alkyl of expression hydrogen atom or carbonatoms 1～6) 3 of expression, the preparation method of 7-dioxo-5 β-cholanic acid or its ester derivative is characterized in that, with following formula (4)
Figure A2005800306300014C5
The courage steroid-4,6 of expression, 24-triolefin-3-ketone epoxy changes into following formula (5)
Figure A2005800306300014C6
6 of expression, 7:24,25-diepoxy courage steroid-4-alkene-3-ketone then carries out hydrogenation, changes into following formula (6)
5 β-24 of expression, 25-epoxy courage steroid-3-ketone-7-alcohol carries out oxidation again, changes into following formula (12)
Figure A2005800306300015C2
5 β-24 of expression, 25-epoxy courage steroid-3, the 7-diketone then is hydrolyzed, and changes into following formula (13)
Figure A2005800306300015C3
5 β-courage the steroid-3 of expression, 7-diketone-24, the 25-glycol carries out oxidation again, according to circumstances carries out esterification again.
21. each is described 3 in the claim 17～20, the preparation method of 7-dioxo-5 β-cholanic acid or its ester derivative is characterized in that, as epoxidizing agent, uses organo-peroxide.
22. claim 21 is described 3, the preparation method of 7-dioxo-5 β-cholanic acid or derivatives thereof is characterized in that, as organo-peroxide, uses general formula A 4CO 3H (in the formula, A 4The alkyl that can be replaced by halogen atom of expression hydrogen atom, carbonatoms 1～20, maybe can have substituent aryl) percarboxylic acids or the general formula A of expression 5(C=NH) OOH (in the formula, A 5The alkyl of expression hydrogen atom, the carbonatoms 1～20 that can be replaced by halogen atom, maybe can have substituent aryl) expression cross imines carboxylic acid or following general formula (14)
Figure A2005800306300015C4
(in the formula, A 6And A 7Represent the alkyl that can be replaced by halogen of carbonatoms 1～20 respectively independently, perhaps also can A 6And A 7Ring texture in conjunction with formation carbonatoms 3～8) the ketone peroxide derivative of expression.
23. claim 21 is described 3, the preparation method of 7-dioxo-5 β-cholanic acid or its ester derivative is characterized in that, as organo-peroxide, uses peroxybenzoic acid or 2-methyl peroxybenzoic acid.
24. claim 23 is described 3, the preparation method of 7-dioxo-5 β-cholanic acid or its ester derivative is characterized in that, adds water in epoxidation reaction.
25. claim 23 is described 3, the preparation method of 7-dioxo-5 β-cholanic acid or its ester derivative is characterized in that, mistake acid concentration and carboxylic acid concentration during with epoxidation reaction remain on below the 0.3M.
26. each is described 3 in the claim 17,18 or 20, the preparation method of 7-dioxo-5 β-cholanic acid or its ester derivative is characterized in that, with following formula (4)
Figure A2005800306300016C1
The courage steroid-4,6 of expression, 24-triolefin-3-ketone halo esterification changes into following formula (15)
Figure A2005800306300016C2
7 of (in the formula, X represents halogen atom, and Y represents the alkyl that can be replaced by halogen of hydrogen atom or carbonatoms 1～10) expression, 24-halo-courage steroid-3-ketone-6, the 25-diol diesters then carries out the basic hydrolysis and the Guan Huan of ester, changes into following formula (5)
Figure A2005800306300016C3
6 of expression, 7:24,25-diepoxy courage steroid-4-alkene-3-ketone.
27. claim 26 described 3, the preparation method of 7-dioxo-5 β-cholanic acid or its ester derivative, it is characterized in that, as the halo esterifying agent, use the halogen positively charged ion propellant of organic carboxyl acid and general formula Z-X (X represents halogen atom in the formula, and Z represents succinimide, phthalic imidine, ethanamide, glycolylurea, tert.-butoxy) expression.
28. each is described 3 in claim 17～20 and 26, the preparation method of 7-dioxo-5 β-cholanic acid or its ester derivative is characterized in that, carries out hydrogenation in the presence of noble metal catalyst.
29. claim 28 described 3, the preparation method of 7-dioxo-5 β-cholanic acid or its ester derivative, it is characterized in that, as noble metal catalyst, use one or two or more kinds the palladium metal be selected from active carbon-supported palladium, alumina load palladium, barium carbonate supported palladium, barium sulfate supported palladium or the lime carbonate supported palladium that pulverous palladium or palladium content are 0.5～50 weight %.
30. claim 28 or 29 described 3, the preparation method of 7-dioxo-5 β-cholanic acid or its ester derivative is characterized in that, in the hydrogenation in the presence of the noble metal catalyst, has alkali simultaneously.
31. claim 30 is described 3, the preparation method of 7-dioxo-5 β-cholanic acid or its ester derivative is characterized in that, as alkali, uses amine.
32. each is described 3 in claim 17～20 and 26, the preparation method of 7-dioxo-5 β-cholanic acid or its ester derivative is characterized in that, carries out the hydrolysis reaction of epoxy in the presence of silica gel or protonic acid.
33. claim 32 described 3, the preparation method of 7-dioxo-5 β-cholanic acid or its ester derivative, it is characterized in that,, use hydrochloric acid, sulfuric acid, nitric acid, perchloric acid, phosphoric acid, phosphorous acid, Hypophosporous Acid, 50, organic carboxyl acid class or organic sulfonic acid class as protonic acid.
34. in claim 17～20 and 26 each described 3, the preparation method of 7-dioxo-5 β-cholanic acid or its ester derivative, it is characterized in that,, use oxyhalogen acids or its salt or molecular state halogen or permanganic acid class, dichromic acid class, chromic acid class as the oxygenant of oxidizing reaction.
35. each is described 3 in claim 17～20 and 26, the preparation method of 7-dioxo-5 β-cholanic acid or its ester derivative is characterized in that, as following formula (4)
Figure A2005800306300017C1
The courage steroid-4,6 of expression, 24-triolefin-3-ketone uses following formula (3)
Figure A2005800306300017C2
The courage steroid-4,7 of expression, 24-triolefin-3-ketone isomerization and the compound that obtains.
36. claim 35 is described 3, the preparation method of 7-dioxo-5 β-cholanic acid or its ester derivative is characterized in that, as following formula (3)
Figure A2005800306300017C3
The courage steroid-4,7 of expression, 24-triolefin-3-ketone uses following formula (2)
The courage steroid-5,7 of expression, 24-triolefin-3 β-pure oxidation and the compound that obtains.
37. following general formula (17)
Figure A2005800306300018C2
(in the formula, R 8Alkyl, alkenyl or the alkynyl of expression hydroxyl, protected hydroxyl, carboxyl, ester group, carbonyl, cyano group, amino or the carbonatoms 1～20 that can be replaced by halogen atom) preparation method of vicinal diol compound of expression; it is characterized in that; with silica gel as catalyzer, with following general formula (16)
Figure A2005800306300018C3
(in the formula, R 8Alkyl, alkenyl or the alkynyl of expression hydroxyl, protected hydroxyl, carboxyl, ester group, carbonyl, cyano group, amino or the carbonatoms 1～20 that can be replaced by halogen atom) the epoxy compounds hydrolysis of expression.
38. following general formula (19)
Figure A2005800306300018C4
(in the formula, St represents to comprise the steroid class skeleton of A ring, B ring, C ring and D ring, and this steroid class skeleton (1) combines with the side chain shown in the formula in the C17 position; (2) on A ring, B ring, C ring and D ring, can have hydroxyl, protected hydroxyl, ketone group or epoxy group(ing); (3) key that is selected between the carbon-to-carbon of one or more positions of C1 position～C8 position can have two keys; (4) the one or more positions that are selected from C4 position, C10 position, C13 position and the C14 position can be by methyl substituted, R 9Expression can have alkylidene group, alkenylene or the alkynylene of the carbonatoms 1～20 of hydroxyl, protected hydroxyl, carboxyl, ester group, carbonyl, cyano group, amino or halogen atom) preparation method of vicinal diol compound of expression; it is characterized in that; with silica gel as catalyzer, with following general formula (18)
(in the formula, St represents to comprise the steroid class skeleton of A ring, B ring, C ring and D ring, and this steroid class skeleton (1) combines with the side chain shown in the formula in the C17 position; (2) on A ring, B ring, C ring and D ring, can have hydroxyl, protected hydroxyl, ketone group or epoxy group(ing); (3) key that is selected between the carbon-to-carbon of one or more positions of C1 position～C8 position can have two keys; (4) the one or more positions that are selected from C4 position, C10 position, C13 position and the C14 position can be by methyl substituted, R 9Expression can have alkylidene group, alkenylene or the alkynylene of the carbonatoms 1～20 of hydroxyl, protected hydroxyl, carboxyl, ester group, carbonyl, cyano group, amino or halogen atom) expression the hydrolysis of steroid class epoxy compounds.
39. following formula (5)
Figure A2005800306300019C1
6 of expression, 7:24,25-diepoxy courage steroid-4-alkene-3-ketone.
40. following formula (10)
Figure A2005800306300019C2
24 of expression, 25-epoxy courage steroid-4,6-diene-3-ketone.
41. following formula (11)
Figure A2005800306300019C3
The courage steroid-4 of expression, 6-diene-3-ketone-24,25-glycol.
42. following formula (6)
Figure A2005800306300019C4
5 β-24 of expression, 25-epoxy courage steroid-3-ketone-7-alcohol.
43. following formula (7)
Figure A2005800306300020C1
5 β-courage steroid-3-the ketone-7,24 of expression, the 25-triol.
44. following formula (9)
Figure A2005800306300020C2
6 of expression, 7-epoxy courage steroid-4-alkene-3-ketone-24,25-glycol.
45. following formula (12)
Figure A2005800306300020C3
5 β-24 of expression, 25-epoxy courage steroid-3,7-diketone.
46. following formula (13)
Figure A2005800306300020C4
5 β-courage the steroid-3 of expression, 7-diketone-24,25-glycol.
47. following formula (15a)
Figure A2005800306300020C5
7 of expression, 24-two chloro-courage steroids-4-alkene-3-ketone-6,25-glycol dicarboxylic acid esters.
48. following formula (20)
Figure A2005800306300021C1
24 of expression, 25-epoxy courage steroid-4-alkene-3-ketone-7-alcohol.
49. following general formula (21a), (21b), (21c) or (21d)
Figure A2005800306300021C2
(in the formula, R 1The alkyl of expression hydrogen atom or carbonatoms 1～6) preparation method of Ursodeoxycholic Acid (UDCA) (21a), gallodesoxycholic acid (21b) or 3 Alpha-hydroxies-7-oxo-5 β-cholanic acid (21c), 7-hydroxyl-3-oxo-5 β-cholanic acid (21d) or these sour ester derivatives of expression, it is characterized in that, will adopt the following general formula (8) of each described method preparation in the claim 17～20,26,35 and 36
(in the formula, R 1The alkyl of expression hydrogen atom or carbonatoms 1～6) 3 of expression, oxidation is according to circumstances carried out in 7-dioxo-5 β-cholanic acid or the reduction of its ester derivative again.
CN 200580030630 2004-07-13 2005-07-12 Method for producing steroid compound Pending CN101018802A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110283224A (en) * 2019-07-16 2019-09-27 湖南华诚生物资源股份有限公司 A kind of semisynthesis of momordica glycoside V
CN113912661A (en) * 2021-11-11 2022-01-11 湖南科瑞生物制药股份有限公司 Synthetic method of 7-hydroxy steroid compound

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110283224A (en) * 2019-07-16 2019-09-27 湖南华诚生物资源股份有限公司 A kind of semisynthesis of momordica glycoside V
CN113912661A (en) * 2021-11-11 2022-01-11 湖南科瑞生物制药股份有限公司 Synthetic method of 7-hydroxy steroid compound

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