CN105732307B - The synthetic method of Maxacalcitol intermediate - Google Patents
The synthetic method of Maxacalcitol intermediate Download PDFInfo
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- CN105732307B CN105732307B CN201610059835.3A CN201610059835A CN105732307B CN 105732307 B CN105732307 B CN 105732307B CN 201610059835 A CN201610059835 A CN 201610059835A CN 105732307 B CN105732307 B CN 105732307B
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
A kind of Maxacalcitol intermediate (3AR; 7AS) the preparation method of-1-((S)-1- (3- hydroxy-3-methyl butoxy) ethyl)-7a- methyl-1 H- indenes-4- alcohol; it include: formula (II) compound in the proton solvent of deprotection agent; the protecting group in formula (II) compound is sloughed, formula (I) compound is obtained.The deprotection agent is CH3OHHCl, proton solvent are methanol.Preparation method of the present invention, easy to operate, the reaction time is short, high income, and no side reaction occurs, and is suitble to large-scale industrial production.
Description
Technical field
The present invention relates to a kind of ((S)-1- (the 3- hydroxy-3-methyl fourth oxygen of Maxacalcitol intermediate (3AR, 7AS)-1-
Base) ethyl) -7a- methyl-1 H- indenes -4- alcohol synthetic method.
Background technique
Maxacalcitol (Maxacalcitol) has strong antiproliferative activity, which is opened by Japanese Chugai company
Hair, and license to other parts of the world production of the Schering Plough company other than Japan.Its injection (trade name Oxarol) in
2000 in Japanese Initial Public Offering, for treating secondary hyperparathyroidism caused by chronic renal failure
(SHPT)；Maxacalcitol ointment was listed in 2001, trade name Oxarol ointment, for treating the chronic eczema class such as psoriasis
Skin disease；In addition, the drug also treats the potentiality of leukaemia, cancer and HTLV-1 infection.Maxacalcitol
(Maxacalcitol) structural formula is as follows:
In the prior art, the preparation of Maxacalcitol is mostly using 1 alpha-dehydroepiandrosterone as raw material, however 1 α-hydroxyl
The research of dehydrobenzene chemical synthesis process is still immature, although advantage that microbial method has a step to introduce 1 α-hydroxyl, but
Its process conditions is harsh, equipment requirement is high, the production cycle is long and inefficiency, is not suitable for industrial production.
(the Stereoselective reduction of C-20ketone of document Steroids 88 (2014) 72-76.
Of vitamin D CD-ring and a new synthetic approach to maxacalcitol) in report as
Lower synthetic method: alcohol 19 obtains compound 23 through bromo, open loop, deprotection, then protects to obtain compound through TEMPO oxidation, TES
25,25 and 26 additions are deprotected to obtain Maxacalcitol again.
The use of 1 alpha-dehydroepiandrosterone is avoided in above-mentioned synthetic method, and uses the 18 (ketone of ketone being more easy to get
18 can be obtained by calciferol through ozonization), ketone 18 is through asymmetric borane reduction, Williamson reaction, lithium aluminium hydride reduction
Reduction, TBAF deprotection, TEMPO oxidation, upper protecting group, witting reaction, TBAF deprotection finally obtain Maxacalcitol,
Compared with illumination heating means, industrial production preferably.
To pass through important intermediate (3AR, 7AS)-1-((S)-1- (3- hydroxyl in the synthesis step of above-mentioned Maxacalcitol
Base -3- methyl butoxy) ethyl) -7a- methyl-1 H- indenes -4- alcohol (compound 23), it is how efficient from the synthesis of compound 22
Compound 23, which just seems, to be even more important.
Synthesize compound 23 from compound 22 has that is, by the silicon-based protecting group on hydroxyl in reaction removal compound 22
Many methods:
Usual way is that compound 22 is added in a solvent, organic acid or inorganic acid is then added, such as formic acid, trifluoro
Acetic acid, acetic acid, hydrogen fluoride, p-methyl benzenesulfonic acid, hydrochloric acid, sulfuric acid etc. remove protected silane base under acid catalysis.But compound 22 divides
There are ehter bonds and the tertiary alcohol in son, and under acidic catalyst, ehter bond can be broken, and the tertiary alcohol can also occur elimination reaction and generate alkene and obtain
By-product (such as following figure), therefore acid catalyzed method synthesis compound 23 is relatively difficult.
In document Steroids 88 (2014) 72-76, it was recently reported that the synthetic method of compound 23, by compound
TBAF (tetrabutyl ammonium fluoride) is added in 22 THF solution, compound 23, final products yield can be obtained in back flow reaction 40h
It is 71%.
This method does not use acidic catalyst, avoids the generation of side reaction, and product yield is higher, but the document is reported
Requirement of the reaction condition to reaction dissolvent it is relatively high, solvent for use tetrahydrofuran will carry out Non-aqueous processing, and reaction speed is too slow,
Time-consuming (reflux 40h), if carrying out industrialized production, the requirement to solvent, equipment is relatively high, and reaction time is too long, at
Originally it is difficult to decrease.
Summary of the invention
It it is an object of the invention to overcome the deficiencies of the prior art and provide a kind of more economical convenience and is suitable for industrial metaplasia
Produce Maxacalcitol intermediate (3AR, 7AS)-1-((S)-1- (3- hydroxy-3-methyl butoxy) ethyl)-7a- methyl-1 H-
The synthetic method of indenes -4- alcohol.
The object of the invention is achieved through the following technical solutions:
A kind of Maxacalcitol intermediate (3AR, 7AS)-1-((S)-1- (3- hydroxy-3-methyl butoxy) ethyl)-7a-
The preparation method of methyl-1 H- indenes -4- alcohol, comprising:
Formula (II) compound sloughs the protecting group in formula (II) compound, obtains formula in the proton solvent of deprotection agent
(I) compound, i.e. intermediate (3AR, 7AS)-1-((S)-1- (3- hydroxy-3-methyl butoxy) ethyl)-7a- methyl-1 H-
Indenes -4- alcohol, the deprotection agent are CH3OHHCl, proton solvent are methanol.
According to the present invention, the deprotection agent is preferably saturated CH3OH·HCl。
According to the present invention, the CH3The volume mass of OHHCl and formula (I) compound is than being preferably 1-10:1, more
Preferably 6:1.
According to the present invention, in the above method, the reaction temperature is 0-40 DEG C, and preferably 20-30 DEG C, the reaction time is preferred
It is 4-10 hours, more preferable 6 hours.
According to the present invention, the above method is preferably and formula (II) compound is added in methanol and is dissolved, then in methyl alcohol
Methanol-hydrogen chloride saturated solution is added.
The present inventor passes through many experiments, has attempted a variety of deprotection agents, it has unexpectedly been discovered that, in methanol-
In hydrogen chloride solution, formula (II) compound Deprotection obtains the higher formula of purity (I) compound, product purity 98.5%, instead
It answers yield to be greater than 80%, is higher than the method reported in document Steroids 88 (2014) 72-76, and without ether in reaction process
Key fracture or hydroxyl eliminate the side reaction at alkene.
Present invention process condition is reasonable, easy to operate, and the reaction time is short, and reaction temperature is low, and reaction yield is high, no side reaction
Occur, is suitble to large-scale industrial production.
Specific embodiment
The present invention is described in detail by following embodiments.But skilled in the art realises that following embodiments are not
Limiting the scope of the invention.Any improvements and changes made on the basis of the present invention, all in protection model of the invention
Within enclosing.
Embodiment 1: methanol/HCl system
The conjunction of (3AR, 7AS)-1-((S)-1- (3- hydroxy-3-methyl butoxy) ethyl)-7a- methyl-1 H- indenes-4- alcohol
At
Formula (II) compound (2g, 5.16mmol) is dissolved in 5ml methanol solution, is added dropwise is saturated to the system at room temperature
CH3OHHCl (12ml), reacts at room temperature 6h after being added dropwise.After complete reaction, it is extracted with ethyl acetate (3x30ml),
Merge organic phase, then washs organic phase, anhydrous sodium sulfate with saturated sodium bicarbonate (30ml) solution, saturated salt solution (2x30ml)
Dry, concentration, column chromatographs (PE/EA=10/1~5/1) purifying, obtains ((S)-1- (the 3- hydroxyl-of white solid (3AR, 7AS)-1-
3- methyl butoxy) ethyl) -7a- methyl-1 H- indenes -4- alcohol 1.197g, yield 83.9%.
Comparative example 1: hydrogen chloride/Tetrahydrofuran System
Formula (II) compound (2g, 5.16mmol) is dissolved in 5ml tetrahydrofuran solution, is added dropwise at room temperature to the system
THFHCl (12ml) reacts at room temperature 6h after being added dropwise, it is complete that TLC monitors unreacted.12h, TLC are reacted in continuation at room temperature
Monitoring has the raw material unreacted of half.It is extracted with ethyl acetate (3x30ml), merges organic phase, then use saturated sodium bicarbonate
(30ml) solution, saturated salt solution (2x30ml) wash organic phase, and anhydrous sodium sulfate is dry, and concentration, column chromatographs (PE/EA=
10/1~5/1) it purifies, obtains white solid (3AR, 7AS)-1-((S)-1- (3- hydroxy-3-methyl butoxy) ethyl)-7a- first
Base -1H- indenes -4- alcohol 0.51g, yield 35.6%.
Comparative example 2: hydrogen chloride/dioxane system
Formula (II) compound (2g, 5.16mmol) is dissolved in 5ml dioxane solution, is added dropwise at room temperature to the system
Isosorbide-5-Nitrae-dioxane HCl (12ml) reacts at room temperature 6h after being added dropwise, it is complete that TLC monitors unreacted.Continue anti-at room temperature
12h is answered, TLC monitoring has 1/3 raw material unreacted.It is extracted with ethyl acetate (3x30ml), merges organic phase, then use unsaturated carbonate
Hydrogen sodium (30ml) solution, saturated salt solution (2x30ml) wash organic phase, and anhydrous sodium sulfate is dry, and concentration, column chromatographs (PE/EA
=10/1~5/1) it purifies, obtains white solid (3AR, 7AS)-1-((S)-1- (3- hydroxy-3-methyl butoxy) ethyl)-7a-
Methyl-1 H- indenes -4- alcohol 0.593g, yield 41.6%.
Comparative example 3: acetic acid/methanol system
Formula (II) compound (2g, 5.16mmol) is dissolved in 10ml methanol solution, second is added dropwise to the system at room temperature
Sour (5ml), reacts at room temperature after being added dropwise, and TLC monitoring raw material unreacted is complete after 1h, while reaction generates product (I), generates
Following ether bond rupture impurity:
After reacting at room temperature 4h, raw material fully reacting, there are also the generations of ether bond rupture impurity except product in addition in reaction solution.Use acetic acid
Ethyl ester (3x30ml) extraction, merges organic phase, then washed with saturated sodium bicarbonate (30ml) solution, saturated salt solution (2x30ml)
Organic phase, anhydrous sodium sulfate is dry, concentration, and column chromatographs (PE/EA=10/1~5/1) purifying, obtains white solid (3AR, 7AS)-
1-((S)-1- (3- hydroxy-3-methyl butoxy) ethyl)-7a- methyl-1 H- indenes-4- alcohol 0.793g, yield 55.6%.
Comparative example 4: sulfuric acid/methanol system
Formula (II) compound (2g, 5.16mmol) is dissolved in 10ml methanol solution, 2M is added dropwise to the system at room temperature
Sulfuric acid (3ml), reacts at room temperature after being added dropwise, and TLC monitoring raw material unreacted is complete after 1h, raw while reaction generates product (I)
At following ether bond rupture impurity:
After reacting at room temperature 3h, raw material fully reacting, there are also the generations of ether bond rupture impurity except product in addition in reaction solution.Use acetic acid
Ethyl ester (3x30ml) extraction, merges organic phase, then washed with saturated sodium bicarbonate (30ml) solution, saturated salt solution (2x30ml)
Organic phase, anhydrous sodium sulfate is dry, concentration, and column chromatographs (PE/EA=10/1~5/1) purifying, obtains white solid (3AR, 7AS)-
1-((S)-1- (3- hydroxy-3-methyl butoxy) ethyl)-7a- methyl-1 H- indenes-4- alcohol 0.677g, yield 47.5%.
Comparative example 5: trifluoroacetic acid/methanol system
Formula (II) compound (2g, 5.16mmol) is dissolved in 10ml methanol solution, is added dropwise three to the system at room temperature
Fluoroacetic acid (2ml), reacts at room temperature after being added dropwise, and TLC monitoring raw material unreacted is complete after 1h, while reaction generates product (I),
Generate following ether bond rupture impurity:
After reacting at room temperature 6h, raw material fully reacting, there are also the generations of ether bond rupture impurity except product in addition in reaction solution.Use acetic acid
Ethyl ester (3x30ml) extraction, merges organic phase, then washed with saturated sodium bicarbonate (30ml) solution, saturated salt solution (2x30ml)
Organic phase, anhydrous sodium sulfate is dry, concentration, and column chromatographs (PE/EA=10/1~5/1) purifying, obtains white solid (3AR, 7AS)-
1-((S)-1- (3- hydroxy-3-methyl butoxy) ethyl)-7a- methyl-1 H- indenes-4- alcohol 0.93g, yield 51.2%.
By above-described embodiment and comparative example it is found that during from formula (II) preparation of compounds of formula (I) compound, only
Use CH3OHHCl could obtain high yield as deprotection agent at room temperature, and without ether bond rupture in reaction process
Or hydroxyl eliminates the side reaction at alkene.
Claims (9)
1. a kind of Maxacalcitol intermediate (3AR, 7AS) -1- ((S) -1- (3- hydroxy-3-methyl butoxy) ethyl) -7a- first
The preparation method of base -1H- indenes -4- alcohol, comprising:
Formula (II) compound sloughs the protecting group in formula (II) compound in the proton solvent of deprotection agent, obtains formula (I) change
Close object, i.e. intermediate (3AR, 7AS)-1-((S)-1- (3- hydroxy-3-methyl butoxy) ethyl)-7a- methyl-1 H- indenes-4-
Alcohol, the deprotection agent are CH3OHHCl, proton solvent are methanol.
2. preparation method according to claim 1, which is characterized in that the deprotection agent is saturation CH3OH·HCl。
3. preparation method according to claim 1 or 2, which is characterized in that the CH3OHHCl and formula (II) compound
Volume mass ratio be 1-10:1.
4. preparation method according to claim 3, which is characterized in that the CH3OHHCl and formula (II) compound
Volume mass ratio is 6:1.
5. preparation method according to claim 1 or 2, which is characterized in that the reaction temperature is 0-40 DEG C.
6. preparation method according to claim 5, which is characterized in that the reaction temperature is 20-30 DEG C.
7. preparation method according to claim 1 or 2, which is characterized in that the reaction time is 4-10 hours.
8. preparation method according to claim 7, which is characterized in that the reaction time is 6 hours.
9. preparation method according to claim 1 or 2, which is characterized in that the method includes adding formula (II) compound
Enter and dissolved into methanol, methanol-hydrogen chloride saturated solution is then added in methyl alcohol.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101434628A (en) * | 2008-12-19 | 2009-05-20 | 浙江博泰化工有限公司 | Process for synthesizing L-beta-5-methyl uracil riboside |
| CN101918358A (en) * | 2007-11-20 | 2010-12-15 | 雅培制药有限公司 | New vitamin D receptor activators and manufacture method |
-
2016
- 2016-01-28 CN CN201610059835.3A patent/CN105732307B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101918358A (en) * | 2007-11-20 | 2010-12-15 | 雅培制药有限公司 | New vitamin D receptor activators and manufacture method |
| CN101434628A (en) * | 2008-12-19 | 2009-05-20 | 浙江博泰化工有限公司 | Process for synthesizing L-beta-5-methyl uracil riboside |
Non-Patent Citations (2)
| Title |
|---|
| 《A New Approach to the Synthesis of the 25-Hydroxy-22-Oxa-Vitamin D3 Side Chain》;Yagamare Fall;《Tetrahedron Letters》;19970707;第38卷(第27期);4909-4912 |
| 《Stereoselective reduction of C-20 ketone of vitamin D CD-ring and a new synthetic approach to maxacalcitol》;Guo-Dong Zhao et al.;《Steroids》;20140717;第88卷;72-76 |
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