CN109503445A - A kind of Alfacalcidol class compound and preparation method thereof - Google Patents
A kind of Alfacalcidol class compound and preparation method thereof Download PDFInfo
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- CN109503445A CN109503445A CN201811571060.3A CN201811571060A CN109503445A CN 109503445 A CN109503445 A CN 109503445A CN 201811571060 A CN201811571060 A CN 201811571060A CN 109503445 A CN109503445 A CN 109503445A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/14—All rings being cycloaliphatic
- C07C2602/24—All rings being cycloaliphatic the ring system containing nine carbon atoms, e.g. perhydroindane
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Abstract
The present invention provides a kind of Alfacalcidol class compound and preparation method thereof, molecular structural formulas are as follows: R is selected fromR1It is selected from
Description
Technical field
The present invention relates to field of pharmaceutical chemistry technology, more particularly to a kind of Alfacalcidol class compound and its preparation side
Method.
Background technique
Alfacalcidol is synthesis of vitamin d, can form activated vitamin D after taking in human body.Vitamin D and parathyroid gland
Element is the element for adjusting human body calcium level.If calcium level is too low, human body will discharge parathormone.Skeleton is calcic
Maximum place is measured, parathormone can make bone calcium enter blood.Calcium plays a crucial role in bodily fuctions, and high calcium can serious shadow
Ring contraction of muscle, nervous function, bone density and clotting mechanism etc..Since the Levels of Parathyroid Hormone of dialysis patient may be because
Human factor increases, and Alfacalcidol can be used to stablize calcium regulating system, and Levels of Parathyroid Hormone is made to remain normal.Ah method's bone
Change alcohol lipophilicity is strong, and solubility in water is extremely low, and poor solubility causes therapeutic effect to decline with dissolution rate, to drug
Clinical expansion causes very big obstacle.Therefore, being improved by structural modification has very high research according to Alfacalcidol water solubility
Value.
Summary of the invention
The purpose of the present invention one is open a kind of Alfacalcidol class compound, water-soluble compared with Alfacalcidol
It is greatly improved, is more advantageous to the clinical use of drug.
To achieve the above object, the present invention provides a kind of Alfacalcidol class compound, molecular structural formulas are as follows:
R is selected fromR1
It is selected from
The purpose of the present invention two is the preparation method of open a kind of Alfacalcidol class compound, to prepare with Ah method
Ostelin is starting material, reacts to obtain target product through 8 steps, and compared with Alfacalcidol, water solubility is greatly improved, and is more had
Conducive to a kind of Alfacalcidol class compound of the clinical use of drug.
To achieve the above object, the present invention provides the preparation method of a kind of Alfacalcidol class compound, chemical equations
Formula are as follows:
In some embodiments, intermediate 1 the preparation method comprises the following steps: reaction flask be added methylene chloride, pyridine, Ah method ossification
Alcohol, paratoluensulfonyl chloride, ice bath, overnight, ice water extracts reaction of going out for magnetic agitation reaction, filters, and filtrate concentration, residue ethyl alcohol is tied again
Crystalline substance obtains white solid.
In some embodiments, intermediate 2 the preparation method comprises the following steps: reaction flask be added dimethyl sulfoxide, intermediate 1, NBS,
Ethyl acetate, the extraction of mixed solution ice water is added in ice bath, illumination condition reaction, and organic layer is concentrated, and residue is directly used in next step
Reaction.
In some embodiments, intermediate 3 the preparation method comprises the following steps: ethyl alcohol is added in reaction flask, intermediate 2, sodium ethoxide adds
Heat reflux, dilute hydrochloric acid tune PH to 7, reaction solution concentration, methylene chloride extraction, merging methylene chloride, ice water washing, organic layer are anhydrous
It is filtered after sodium sulphate is dry, filtrate concentration, residue recrystallizing methanol obtains white solid.
In some embodiments, intermediate 4 the preparation method comprises the following steps: intermediate 3 is added in reaction flask, acetone, bromobenzyl is anhydrous
Potassium carbonate, potassium iodide are stirred at reflux reaction, water are added after reaction solution concentration, and ethyl acetate extraction is secondary, does after organic layer washing
It is dry, it filters, silica gel column chromatography obtains thick liquid.
In some embodiments, intermediate 5 the preparation method comprises the following steps: intermediate 4 is dissolved in tetrahydrofuran, trifluoro second is added dropwise
Tetrahydrofuran and unreacted trifluoroacetic acid is removed under reduced pressure in acid, back flow reaction, and residue ethyl alcohol recrystallization obtains white solid.
In some embodiments, intermediate F-1's the preparation method comprises the following steps: ethyl acetate is added in reaction flask, sequentially adds
Mesosome 5, PPh3,2- morpholine ethanol and DIAD, are stirred at room temperature after charging, and TLC judgement reaction terminates, and reaction solution is poured into ice
Water, filters, and filter cake is dried in vacuo to obtain white solid.
In some embodiments, intermediate F-2's the preparation method comprises the following steps: intermediate F-1 and methanol, stirring is added in reaction flask
Dissolution continuously adds 5%Pd/C, and normal pressure hydrogenation reaction filters, and filtrate concentration, residue acetone recrystallization obtains white solid.
In some embodiments, intermediate F's the preparation method comprises the following steps: reaction flask be added ethyl acetate, sequentially add centre
Body F-2, PPh3, ethylene glycol and DIAD, are stirred at room temperature after charging, and TLC judgement reaction terminates, and reaction solution is poured into ice water,
It filters, filter cake is dried in vacuo to obtain white solid.
Compared with prior art, the beneficial effects of the present invention are: one kind Alfacalcidol class compound provided by the invention
And preparation method thereof, using Alfacalcidol as starting material, react to obtain target product through 8 steps, it is water-soluble compared with Alfacalcidol
Property is greatly improved, and is more advantageous to the clinical use of drug.
Specific embodiment
Below with reference to each embodiment, the present invention is described in detail, but it should be stated that, these embodiments are simultaneously
Non- limitation of the present invention, those of ordinary skill in the art are according to these embodiments in made function, method or structure
Equivalent transformation or substitution, all belong to the scope of protection of the present invention within.
Embodiment one:
Present embodiment discloses a kind of Alfacalcidol class compound, molecular structural formulas are as follows:
R is selected fromR1
It is selected from
Embodiment two:
Present embodiment discloses the preparation method of a kind of Alfacalcidol class compound, chemical equations are as follows:
Intermediate 1 the preparation method comprises the following steps: 250ml reaction flask be added methylene chloride 100ml, pyridine 2ml, Alfacalcidol
4.12g, paratoluensulfonyl chloride 4g, ice bath, overnight, 5ml ice water extracts reaction of going out for magnetic agitation reaction, filters, filtrate concentration, residue
Ethyl alcohol recrystallization obtains white solid 5.9g.
1 molecular structural formula of intermediate are as follows:
Intermediate 2 the preparation method comprises the following steps: 100ml reaction flask be added dimethyl sulfoxide 50ml, 7.22g intermediate 1, NBS2.5g,
Ice bath, illumination condition react 4h, and ethyl acetate 50ml is added, and mixed solution ice water extracts 3 times, organic layer concentration, and residue is direct
For reacting in next step.
2 molecular structural formula of intermediate are as follows:
Intermediate 3 the preparation method comprises the following steps: ethyl alcohol 50ml, the intermediate 2 and second of the reaction of upper step is added in 100ml reaction flask
Sodium alkoxide 1g is heated to reflux 4h, dilute hydrochloric acid tune PH to 7, and reaction solution is concentrated, and methylene chloride 20ml is extracted 3 times, merges methylene chloride,
Ice water washing filters after organic layer anhydrous sodium sulfate is dry, and filtrate concentration, residue recrystallizing methanol obtains white solid 6.3g.
3 molecular structural formula of intermediate are as follows:
Intermediate 4 the preparation method comprises the following steps: 100ml reaction flask is added 5.2g intermediate 3 and acetone 60ml, bromobenzyl 5ml is anhydrous
Potassium carbonate 2.6g, potassium iodide 0.5g are stirred at reflux reaction 6h, 20ml water are added after reaction solution concentration, and ethyl acetate extraction is secondary,
It is dry after organic layer washing, it filters, silica gel column chromatography obtains 5.5g thick liquid.
4 molecular structural formula of intermediate are as follows:
Intermediate 5 the preparation method comprises the following steps: 12.2g intermediate 4 is dissolved in 100ml tetrahydrofuran, trifluoroacetic acid 10ml is added dropwise, returns
Stream reaction 4h, is removed under reduced pressure tetrahydrofuran and unreacted trifluoroacetic acid, residue ethyl alcohol recrystallization obtains white solid 7.35g.
5 molecular structural formula of intermediate are as follows:
Intermediate F-1's the preparation method comprises the following steps: 100ml reaction flask be added be added ethyl acetate 50ml, sequentially add in 5.8g
2h, TLC judgement reaction knot is stirred at room temperature in mesosome 5,11.6g PPh3,6.8g2- morpholine ethanol and 4mlDIAD after charging
Reaction solution is poured into ice water by beam, is filtered, and filter cake is dried in vacuo to obtain white solid 5.35g.
Intermediate F-1 molecular structural formula are as follows:
Intermediate F-2's the preparation method comprises the following steps: 6.8g intermediate W3-1 and 100ml methanol is added in 250ml reaction flask, is stirred molten
Solution, continuously adds 5%Pd/C 0.5g, and normal pressure hydrogenation reacts 2h.It filters, filtrate concentration, residue acetone recrystallization obtains white solid
4.1g。
Intermediate F-2 molecular structural formula are as follows:
Intermediate F's the preparation method comprises the following steps: 100ml reaction flask be added be added ethyl acetate 50ml, sequentially add among 5.85g
Body 5,11.6g PPh3,24g ethylene glycol and 4mlDIAD, are stirred at room temperature 2h after charging, TLC judgement reaction terminates, will react
Liquid pours into ice water, filters, and filter cake is dried in vacuo to obtain white solid 6.01g.
Intermediate F molecular structural formula are as follows:
Embodiment three:
Present embodiment discloses the preparation method of a kind of Alfacalcidol class compound, chemical equations are as follows:
Intermediate 1 the preparation method comprises the following steps: 250ml reaction flask be added methylene chloride 100ml, pyridine 2ml, Alfacalcidol
4.12g, paratoluensulfonyl chloride 4g, ice bath, overnight, 5ml ice water extracts reaction of going out for magnetic agitation reaction, filters, filtrate concentration, residue
Ethyl alcohol recrystallization obtains white solid 5.9g.
1 molecular structural formula of intermediate are as follows:
Intermediate 2 the preparation method comprises the following steps: 100ml reaction flask be added dimethyl sulfoxide 50ml, 7.22g intermediate 1, NBS2.5g,
Ice bath, illumination condition react 4h, and ethyl acetate 50ml is added, and mixed solution ice water extracts 3 times, organic layer concentration, and residue is direct
For reacting in next step.
2 molecular structural formula of intermediate are as follows:
Intermediate 3 the preparation method comprises the following steps: ethyl alcohol 50ml, the intermediate 2 and second of the reaction of upper step is added in 100ml reaction flask
Sodium alkoxide 1g is heated to reflux 4h, dilute hydrochloric acid tune PH to 7, and reaction solution is concentrated, and methylene chloride 20ml is extracted 3 times, merges methylene chloride,
Ice water washing filters after organic layer anhydrous sodium sulfate is dry, and filtrate concentration, residue recrystallizing methanol obtains white solid 6.3g.
3 molecular structural formula of intermediate are as follows:
Intermediate 4 the preparation method comprises the following steps: 100ml reaction flask is added 5.2g intermediate 3 and acetone 60ml, bromobenzyl 5ml is anhydrous
Potassium carbonate 2.6g, potassium iodide 0.5g are stirred at reflux reaction 6h, 20ml water are added after reaction solution concentration, and ethyl acetate extraction is secondary,
It is dry after organic layer washing, it filters, silica gel column chromatography obtains 5.5g thick liquid.
4 molecular structural formula of intermediate are as follows:
Intermediate 5 the preparation method comprises the following steps: 12.2g intermediate 4 is dissolved in 100ml tetrahydrofuran, trifluoroacetic acid 10ml is added dropwise, returns
Stream reaction 4h, is removed under reduced pressure tetrahydrofuran and unreacted trifluoroacetic acid, residue ethyl alcohol recrystallization obtains white solid 7.35g.
5 molecular structural formula of intermediate are as follows:
Intermediate F-1's the preparation method comprises the following steps: 100ml reaction flask be added ethyl alcohol 50ml, sequentially add 5.85g intermediate 5,
2h, TLC judgement reaction knot is stirred at room temperature in 11.6g PPh3,6.4g2- ethoxy nafoxidine and 4mlDIAD after charging
Reaction solution is poured into ice water by beam, is filtered, and filter cake ethyl alcohol recrystallization obtains white solid 5.14g.
Intermediate F-1 molecular structural formula are as follows:
Intermediate F-2's the preparation method comprises the following steps: 5.2g intermediate W6-1 and 100ml methanol is added in 250ml reaction flask, is stirred molten
Solution, continuously adds 5%Pd/C 0.5g, and normal pressure hydrogenation reacts 2h.It filters, filtrate concentration, residue acetone recrystallization obtains white solid
4.45g。
Intermediate F-2 molecular structural formula are as follows:
Intermediate F's the preparation method comprises the following steps: 100ml reaction flask be added be added ethyl acetate 50ml, sequentially add among 5.85g
2h is stirred at room temperature in body 5,11.6g PPh3,3.6g glycerine pure and mild 4mlDIAD after charging, TLC judgement reaction terminates, will
Reaction solution pours into ice water, filters, and filter cake is dried in vacuo to obtain white solid 6.11g.
Intermediate F molecular structural formula are as follows:
Soluble test data are as follows:
The series of detailed descriptions listed above only for feasible embodiment of the invention specifically
Protection scope bright, that they are not intended to limit the invention, it is all without departing from equivalent implementations made by technical spirit of the present invention
Or change should all be included in the protection scope of the present invention.
In addition, it should be understood that although this specification is described in terms of embodiments, but not each embodiment is only wrapped
Containing an independent technical solution, this description of the specification is merely for the sake of clarity, and those skilled in the art should
It considers the specification as a whole, the technical solutions in the various embodiments may also be suitably combined, forms those skilled in the art
The other embodiments being understood that.
Claims (10)
1. a kind of Alfacalcidol class compound, which is characterized in that its molecular structural formula are as follows:
R is selected from
R1It is selected from
2. the preparation method of one kind Alfacalcidol class compound according to claim 1, which is characterized in that chemical equation
Formula are as follows:
3. the preparation method of one kind Alfacalcidol class compound according to claim 2, which is characterized in that intermediate 1
The preparation method comprises the following steps: methylene chloride is added in reaction flask, pyridine, Alfacalcidol, paratoluensulfonyl chloride, ice bath, magnetic agitation is anti-
It should stay overnight, ice water extracts reaction of going out, and filters, and filtrate concentration, residue ethyl alcohol recrystallization obtains white solid.
4. the preparation method of one kind Alfacalcidol class compound according to claim 3, which is characterized in that intermediate 2
The preparation method comprises the following steps: reaction flask be added dimethyl sulfoxide, intermediate 1, NBS, ice bath, illumination condition reaction, be added ethyl acetate, mix
The extraction of solution ice water is closed, organic layer concentration, residue is directly used in react in next step.
5. the preparation method of one kind Alfacalcidol class compound according to claim 4, which is characterized in that intermediate 3
The preparation method comprises the following steps: ethyl alcohol is added in reaction flask, intermediate 2, sodium ethoxide is heated to reflux, dilute hydrochloric acid tune PH to 7, reaction solution concentration,
Methylene chloride extraction merges methylene chloride, and ice water washing filters after organic layer anhydrous sodium sulfate is dry, filtrate concentration, residue first
Alcohol recrystallization, obtains white solid.
6. the preparation method of one kind Alfacalcidol class compound according to claim 5, which is characterized in that intermediate 4
The preparation method comprises the following steps: intermediate 3 is added in reaction flask, acetone, bromobenzyl, Anhydrous potassium carbonate, potassium iodide is stirred at reflux reaction, reaction
Water is added after liquid concentration, ethyl acetate extraction is secondary, and it is dry after organic layer washing, it filters, silica gel column chromatography obtains thick liquid.
7. the preparation method of one kind Alfacalcidol class compound according to claim 6, which is characterized in that intermediate 5
The preparation method comprises the following steps: intermediate 4 is dissolved in tetrahydrofuran, be added dropwise trifluoroacetic acid, tetrahydrofuran and not instead is removed under reduced pressure in back flow reaction
The trifluoroacetic acid answered, residue ethyl alcohol recrystallization, obtains white solid.
8. the preparation method of one kind Alfacalcidol class compound according to claim 7, which is characterized in that intermediate F-
1 the preparation method comprises the following steps: reaction flask be added ethyl acetate, sequentially add intermediate 5, PPh3,2- morpholine ethanol and DIAD, fed
It is stirred at room temperature after finishing, TLC judgement reaction terminates, and reaction solution is poured into ice water, is filtered, filter cake is dried in vacuo to obtain white solid.
9. the preparation method of one kind Alfacalcidol class compound according to claim 8, which is characterized in that intermediate F-
2 the preparation method comprises the following steps: intermediate F-1 and methanol, stirring and dissolving is added in reaction flask, continuously add 5%Pd/C, normal pressure hydrogenation is anti-
It answers, filters, filtrate concentration, residue acetone recrystallization obtains white solid.
10. the preparation method of one kind Alfacalcidol class compound according to claim 9, which is characterized in that intermediate F
The preparation method comprises the following steps: reaction flask be added ethyl acetate, sequentially add intermediate F-2, PPh3, ethylene glycol and DIAD, charging finishes
After be stirred at room temperature, TLC judgement reaction terminates, and reaction solution is poured into ice water, is filtered, filter cake is dried in vacuo to obtain white solid.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114656413A (en) * | 2022-03-30 | 2022-06-24 | 南通华山药业有限公司 | Alfacalcidol heterocyclic ester derivative and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103073469A (en) * | 2013-01-16 | 2013-05-01 | 青岛正大海尔制药有限公司 | Preparation method for alfacalcidol |
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2018
- 2018-12-21 CN CN201811571060.3A patent/CN109503445A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103073469A (en) * | 2013-01-16 | 2013-05-01 | 青岛正大海尔制药有限公司 | Preparation method for alfacalcidol |
Non-Patent Citations (2)
| Title |
|---|
| JIE JACK LI著: "《有机人名反应及机理》", 30 September 2003, 华东理工大学出版社 * |
| 熊前程编: "《有机化学》", 31 August 2018, 西安交通大学出版社 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114656413A (en) * | 2022-03-30 | 2022-06-24 | 南通华山药业有限公司 | Alfacalcidol heterocyclic ester derivative and preparation method thereof |
| CN114656413B (en) * | 2022-03-30 | 2024-04-09 | 南通华山药业有限公司 | Alfacalcidol heterocyclic ester derivative and preparation method thereof |
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Application publication date: 20190322 |