CN106748642A - A kind of synthetic method of doxercalciferol analog WXFQ 65 - Google Patents
A kind of synthetic method of doxercalciferol analog WXFQ 65 Download PDFInfo
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- CN106748642A CN106748642A CN201611065068.3A CN201611065068A CN106748642A CN 106748642 A CN106748642 A CN 106748642A CN 201611065068 A CN201611065068 A CN 201611065068A CN 106748642 A CN106748642 A CN 106748642A
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- doxercalciferol
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- NEETXMRNUNEBRH-JCDCZUNOSA-N CC(C)[C@@H](C)CC[C@@H](C)C(CC1)[C@@](C)(CCC2)C1/C2=C/C=C(/C[C@H](C[C@@H]1O)O)\C1=C Chemical compound CC(C)[C@@H](C)CC[C@@H](C)C(CC1)[C@@](C)(CCC2)C1/C2=C/C=C(/C[C@H](C[C@@H]1O)O)\C1=C NEETXMRNUNEBRH-JCDCZUNOSA-N 0.000 description 1
- 0 CC(C)[C@@](C)C=C[C@@](C)C(CC1)[C@@](C)(CCC2*)C1C2=C=C=C(C(C)[C@](C1)O)C(*)[C@@]1O Chemical compound CC(C)[C@@](C)C=C[C@@](C)C(CC1)[C@@](C)(CCC2*)C1C2=C=C=C(C(C)[C@](C1)O)C(*)[C@@]1O 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/09—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/62—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/74—Separation; Purification; Use of additives, e.g. for stabilisation
- C07C29/76—Separation; Purification; Use of additives, e.g. for stabilisation by physical treatment
- C07C29/78—Separation; Purification; Use of additives, e.g. for stabilisation by physical treatment by condensation or crystallisation
Abstract
The invention provides a kind of synthetic method of doxercalciferol analog WXFQ 65, it uses the excessive halogenating agent to carry out halogenating reaction in organic solvent to doxercalciferol, it is subsequently adding hydrolysing agent and the reaction that is hydrolyzed in acid condition, and carries out being recrystallized to give doxercalciferol analog WXFQ 65 by adding recrystallization reagent.In the present invention, using excessive halogenating agent to being hydrolyzed again after doxercalciferol halo, and by being recrystallized to give final product, avoid and aoxidized using hypertoxic raw material selenium dioxide, and product optical activity is good, building-up process step is short, mild condition, building-up process environmental protection is simultaneously suitable to industrialized production, and the water solubility of the doxercalciferol analog WXFQ 65 for finally preparing preferably improves the absorptivity in human body.
Description
Technical field
The present invention relates to biomedicine technical field, more particularly to a kind of synthesis side of doxercalciferol analog WXFQ-65
Method.
Background technology
Vitamin d compounds are clinically mainly used in treating osteoporosis, and key agents have calcitriol, Ah method's bone
Change alcohol, doxercalciferol etc., wherein doxercalciferol is free from side effects to the hemodialysis patients with Secondary Hyperparathyroidism and extensively should
With.Doxercalciferol can not only promote Calcium and phosphorous absorption to treat osteoporosis, also thin with inducing apoptosis of tumour cell, suppression tumour
The effects such as dysuria with lower abdominal colic shifting.
Vitamin d compounds can not only promote absorption of the bone to calcium phosphorus, it is ensured that the ample supply of internal calcium phosphorus, promote
Enter the normal calcification of bone, also with more extensive biological effect, such as suppress cell propagation, Cell differentiation inducing activity, regulation
Body immune system etc..Research shows that vitamin D does not possess physiological function in itself, is only converted into corresponding activity form, such as
The normal physiological action of the competence exertions such as 1 alpha-hydroxy vitamin D.Vitamin D is in vivo for the process of 1 alpha-hydroxy vitamin D is received
Many factors influence, and tend not to provide enough active bodies.Therefore, study 1 alpha-hydroxy vitamin D class compound and its be similar to
Thing is significant.The doxercalciferol of existing document report and the preparation method of Alfacalcidol are cumbersome, and synthesis is difficult
Road is also very big.Meanwhile, the ketone toxic reagent such as acetone, butanone is needed to use in the synthetic route of existing doxercalciferol, and make
With poisonous selenium dioxide as oxidant, therefore environmental protection is had significant effect；Meanwhile, the poisonous examination of the ketone such as acetone, butanone
Agent can produce certain harm in industrialization to human body.Finally, the optical activity of traditional doxercalciferol is less desirable, and
There is the defect of poorly water-soluble.
In view of this, it is necessary to which doxercalciferol of the prior art and its synthetic route are improved, it is above-mentioned to solve
Problem.
The content of the invention
It is an object of the invention to disclose a kind of synthetic method of doxercalciferol analog WXFQ-65, it is to avoid synthetic route
The toxic reagents such as middle use ketone, reduce synthesis difficulty, improve optical activity and water solubility.
For achieving the above object, the invention provides a kind of synthetic method of doxercalciferol analog WXFQ-65, should
Synthetic method is：Halogenating reaction is carried out using excessive halogenating agent in organic solvent to doxercalciferol, hydrolysis is subsequently adding
Reagent and the reaction that is hydrolyzed in acid condition, and be similar to by adding recrystallization reagent be recrystallized to give doxercalciferol
Thing WXFQ-65, the chemical equation of the synthetic method is：
As a further improvement on the present invention, the halogenating agent is NBS, Br2Or Cl2。
As a further improvement on the present invention, the temperature of the halogenating reaction be 0 DEG C to reflux temperature, the hydrolysis
Temperature be room temperature to reflux temperature.
As a further improvement on the present invention, the organic solvent be selected from carbon tetrachloride, normal heptane, n-hexane, hexamethylene,
The mixture of one or several any ratios in tetrahydrofuran, dioxane, methyl alcohol, ethanol, water.
As a further improvement on the present invention, the halogenating agent and the mol ratio of doxercalciferol are 1:0.5~1:20.
As a further improvement on the present invention, the halogenating agent and the mol ratio of doxercalciferol are 1:8~1:10.
As a further improvement on the present invention, the hydrolysing agent is selected from ethyl acetate, dichloromethane, chloroform, ethanol, first
The mixture of one or several any ratios in alcohol, tetrahydrofuran, dioxane.
As a further improvement on the present invention, the recrystallization reagent is selected from acetonitrile, water, methyl alcohol, ethanol, tetrahydrofuran
One or several any ratios mixture.
As a further improvement on the present invention, the recrystallization reagent is the mixture of acetonitrile and water, the acetonitrile and water
Mol ratio be 8:1.
As a further improvement on the present invention, it is added dropwise hydrochloric acid, sulfuric acid or acetic acid after hydrolysing agent is added, and by pH value
Control is between 3~6.
Compared with prior art, the beneficial effects of the invention are as follows：In the present invention, it is ossified to degree using excessive halogenating agent
Hydrolyzed again after alcohol halo, and by being recrystallized to give final product, it is to avoid aoxidized using hypertoxic raw material selenium dioxide, and
Product optical activity is good, and building-up process step is short, mild condition, and building-up process environmental protection is simultaneously suitable to industrialized production, finally prepares
The water solubility of the doxercalciferol analog WXFQ-65 for obtaining preferably, improves the absorptivity in human body.
Specific embodiment
With reference to each implementation method, the present invention is described in detail, but it should explanation, these implementation methods are simultaneously
Non- limitation of the present invention, those of ordinary skill in the art are according in these implementation method institutes works energy, method or structure
Equivalent transformation or replacement, belong within protection scope of the present invention.
Unless there is specified otherwise in specification, component, the raw material in each embodiment in the present invention are pure using analysis
Rank.In addition, " g " in each embodiment is unit of weight " gram "；" h " is chronomere's " hour "；" ml " is volume unit " milli
Rise "；" room temperature " is 23 DEG C.
The invention provides a kind of synthetic method of doxercalciferol analog WXFQ-65, the synthetic method is：Using excess
Halogenating agent halogenating reaction is carried out in organic solvent to doxercalciferol, be subsequently adding hydrolysing agent and enter in acid condition
Row hydrolysis, and carry out being recrystallized to give doxercalciferol analog WXFQ-65, the synthesis side by adding recrystallization reagent
The chemical equation of method is：
Preferably, the halogenating agent is NBS, Br2Or Cl2, and most preferably NBS.The halogenating agent is NBS, Br2
Or Cl2, and most preferably NBS.It should be noted that in each embodiment of this specification, it is only exemplary to show NBS, Br2
Or Cl2Used as the raw material of halogenating reaction, those skilled in the art can be arrived with reasonable prediction, other halogen simple substance or contain halogen
And suitable for the compound of substitution reaction.
Preferably, the temperature of the halogenating reaction is for 0 DEG C to reflux temperature, and most preferably reflux temperature；The hydrolysis
The temperature of reaction be room temperature to reflux temperature, and most preferably reflux temperature.
Preferably, the organic solvent is selected from carbon tetrachloride, normal heptane, n-hexane, hexamethylene, tetrahydrofuran, dioxy six
The mixture of one or several any ratios in ring, methyl alcohol, ethanol, water, and most preferably dioxane.
Preferably, the halogenating agent and the mol ratio of doxercalciferol are 1:0.5~1:20, and more preferably 1:8
~1:10.
Preferably, the hydrolysing agent is selected from ethyl acetate, dichloromethane, chloroform, ethanol, methyl alcohol, tetrahydrofuran, dioxy
The mixture of one or several any ratios in six rings, and most preferably ethanol.
Preferably, it is described recrystallization reagent be selected from acetonitrile, water, methyl alcohol, ethanol, tetrahydrofuran in one or several
The mixture of what ratio, and the more preferably mixture of acetonitrile and water, the acetonitrile is 8 with the mol ratio of water:1.
Preferably, in hydrolysis can by the way that hydrochloric acid, sulfuric acid or acetic acid is added dropwise, to adjust the pH value of hydrolysis,
And the pH value of hydrolysis can be controlled between 3~6.
Embodiment one：
The first step：Synthetic bromide is for doxercalciferol.
Dioxane 100ml is added in 250ml three-necked bottles, then is separately added into doxercalciferol 42.4g and NBS178g, risen
Be positioned over for three-necked bottle 6-8h stirred in electromagnetic mixing apparatus by temperature to reflux temperature, stops heating, is cooled to room temperature (23 DEG C),
Reaction solution after the being sufficiently stirred for suction filtration in Vacuum filtration device, then concentrates filtrate, and gained enriched product does not refine direct
For next step reaction.In the process, in doxercalciferol on two positions hydrogen ion is substituted, to form intermediate product bromo
Doxercalciferol.NBS (N- bromo-succinimides) is a very useful bromating agent, and it has the selectivity of height, an attack
α-H the covalent bonds that weak c h bond, i.e. attack are connected with double bond or phenyl ring.
Second step：Synthesis doxercalciferol analog WXFQ-65.
Previous step concentration gained bromo doxercalciferol 400ml ethanol dissolves, and is transferred in 1L there-necked flasks, then, is added dropwise
Concentrated hydrochloric acid 3ml to ensure hydrolysing agent and the reaction that is hydrolyzed in acid condition, and by the pH value control of solution 3~6 it
Between, electromagnetic agitation reaction 6h stops heating, is cooled to room temperature, and reaction solution concentration adds the recrystallization being made up of acetonitrile and water
Reagent is recrystallized, to obtain white solid 20.3g, as final product doxercalciferol analog WXFQ-65.Specifically,
Acetonitrile and the mol ratio of water are 8 in the recrystallization reagent:1.The concentration of above-mentioned concentrated hydrochloric acid is 70wt%.
The physical constant of the preparation-obtained doxercalciferol analog WXFQ-65 of the present embodiment is：
1H NMR(400MHZ,CHCl3)：6.42 (1H, d), 5.99 (1H, d), 5.38 (2H, d), 5.14 (2H, d), 4.72
(1H, m), 4.26 (1H, m), 2.92 (1H, m), 2.58 (1H, m), 2.30 (1H, m, 0.92 (3H, d), 0.87 (8H, m).m/z：
445.84[M+1]。
Embodiment two：
The first step：Synthetic bromide is for doxercalciferol.
Carbon tetrachloride 100ml is added in 250ml three-necked bottles, then is separately added into doxercalciferol 40.8g and NBS180g, risen
Be positioned over for three-necked bottle 12h stirred in electromagnetic mixing apparatus by temperature to reflux temperature, stops heating, is cooled to room temperature (23 DEG C), fills
The reaction solution divided after stirring suction filtration in Vacuum filtration device, then concentrates filtrate, and gained enriched product is not refined and directly used
In next step reaction.In the process, in doxercalciferol on two positions hydrogen ion is substituted, to form intermediate product bromo degree
Ostelin.
Second step：Synthesis doxercalciferol analog WXFQ-65.
Previous step concentration gained bromo doxercalciferol 500ml tetrahydrofurans dissolve, and are transferred in 1L there-necked flasks, then,
Concentrated hydrochloric acid 3ml is added dropwise to ensure hydrolysing agent and the reaction that is hydrolyzed in acid condition, and the pH value of solution is controlled 3~
Between 6, and most preferably pH value is 3, and electromagnetic agitation reaction 6h stops heating, is cooled to room temperature (23 DEG C), and reaction solution concentration adds
Enter the recrystallization reagent being made up of ethanol and water to be recrystallized, to obtain white solid 18.8g, as final product degree bone
Change alcohol analog WXFQ-65.Specifically, ethanol and the mol ratio of water are 10 in the recrystallization reagent:1.Above-mentioned concentrated hydrochloric acid it is dense
It is 70wt% to spend.
The physical constant of the preparation-obtained doxercalciferol analog WXFQ-65 of the present embodiment is：
1H NMR(400MHZ,CHCl3)：6.43 (1H, d), 5.98 (1H, d), 5.37 (2H, d), 5.162H, d), 4.72
(1H, m), 4.25 (1H, m), 2.92 (1H, m), 2.58 (1H, m), 2.30 (1H, m, 0.92 (3H, d), 0.87 (8H, m).m/z：
445.83[M+1]。
Embodiment three：
The first step：Synthesis chloro doxercalciferol.
N-hexane 100ml is added in 250ml three-necked bottles, then is separately added into doxercalciferol 46.2g and chlorine 2000ml, risen
Be positioned over for three-necked bottle 12h stirred in electromagnetic mixing apparatus by temperature to reflux temperature, stops heating, is cooled to room temperature (23 DEG C), fills
The reaction solution divided after stirring suction filtration in Vacuum filtration device, then concentrates filtrate, and gained enriched product is not refined and directly used
In next step reaction.In the process, in doxercalciferol on two positions hydrogen ion is substituted, to form intermediate product chloro degree
Ostelin.
Second step：Synthesis doxercalciferol analog WXFQ-65.
Previous step concentration gained chloro doxercalciferol 500ml chloroforms dissolve, and are transferred in 1L there-necked flasks, then, are added dropwise
2~3ml of the concentrated sulfuric acid is controlled 3~6 the pH value of solution with ensuring hydrolysing agent and the reaction that is hydrolyzed in acid condition
Between, and most preferably pH value is 3, electromagnetic agitation reaction 10h, stops heating, is cooled to room temperature (23 DEG C), reaction solution concentration adds
Enter the recrystallization reagent being made up of methyl alcohol, ethanol and water to be recrystallized, it is as final to produce to obtain white solid 20.2g
Thing doxercalciferol analog WXFQ-65.Specifically, methyl alcohol in the recrystallization reagent：Ethanol：The mol ratio of water is 10:2：1.On
The concentration of the concentrated sulfuric acid is stated for more than 90wt%, and does not select oleum.
The physical constant of the preparation-obtained doxercalciferol analog WXFQ-65 of the present embodiment is：
1H NMR(400MHZ,CHCl3)：6.45 (1H, d), 5.98 (1H, d), 5.38 (2H, d), 5.162H, d), 4.74
(1H, m), 4.26 (1H, m), 2.92 (1H, m), 2.58 (1H, m), 2.30 (1H, m, 0.92 (3H, d), 0.87 (8H, m).m/z：
445.89[M+1]。
The synthetic method of the doxercalciferol analog WXFQ-65 shown by various embodiments of the present invention has synthetic route short,
Do not use toxic reagent, it is easy to operate.Found in the follow-up study to the route, have many in the preparation process of doxercalciferol
These analogs (doxercalciferol analog WXFQ-65) are separated and identified and through preliminary by individual new doxercalciferol analog generation
Pharmacological Activity Screening, activity increases by 8.9 times compared with traditional doxercalciferol, and water solubility is the 98.1 of traditional doxercalciferol
Times；It is water-soluble it is too low be doxercalciferol preparation research major obstacle, doxercalciferol analog WXFQ-65 not only increases work
Property, the preparation problem of the medicine is also solved, can be made into tablet, electuary, capsule.
Those listed above is a series of to be described in detail only for feasibility implementation method of the invention specifically
Bright, they simultaneously are not used to limit the scope of the invention, all equivalent implementations made without departing from skill spirit of the present invention
Or change should be included within the scope of the present invention.
It is obvious to a person skilled in the art that the invention is not restricted to the details of above-mentioned one exemplary embodiment, Er Qie
In the case of without departing substantially from spirit or essential attributes of the invention, the present invention can be in other specific forms realized.Therefore, no matter
From the point of view of which point, embodiment all should be regarded as exemplary, and be nonrestrictive, the scope of the present invention is by appended power
Profit requires to be limited rather than described above, it is intended that all in the implication and scope of the equivalency of claim by falling
Change is included in the present invention.
Moreover, it will be appreciated that although the present specification is described in terms of embodiments, not each implementation method is only wrapped
Containing an independent technical scheme, this narrating mode of specification is only that for clarity, those skilled in the art should
Specification an as entirety, the technical scheme in each embodiment can also be formed into those skilled in the art through appropriately combined
May be appreciated other embodiment.
Claims (10)
1. a kind of synthetic method of doxercalciferol analog WXFQ-65, it is characterised in that the synthetic method is：Using excess
Halogenating agent carries out halogenating reaction in organic solvent to doxercalciferol, is subsequently adding hydrolysing agent and carries out in acid condition
Hydrolysis, and carry out being recrystallized to give doxercalciferol analog WXFQ-65, the synthetic method by adding recrystallization reagent
Chemical equation be：
2. synthetic method according to claim 1, it is characterised in that the halogenating agent is NBS, Br2Or Cl2。
3. synthetic method according to claim 1, it is characterised in that the temperature of the halogenating reaction is 0 DEG C to the temperature that flows back
Degree, the temperature of the hydrolysis is room temperature to reflux temperature.
4. synthetic method according to claim 1, it is characterised in that the organic solvent be selected from carbon tetrachloride, normal heptane,
The mixture of one or several any ratios in n-hexane, hexamethylene, tetrahydrofuran, dioxane, methyl alcohol, ethanol, water.
5. synthetic method according to claim 1, it is characterised in that the halogenating agent is with the mol ratio of doxercalciferol
1:0.5~1:20.
6. synthetic method according to claim 5, it is characterised in that the halogenating agent is with the mol ratio of doxercalciferol
1:8~1:10.
7. synthetic method according to claim 1, it is characterised in that the hydrolysing agent is selected from ethyl acetate, dichloromethane
The mixture of one or several any ratios in alkane, chloroform, ethanol, methyl alcohol, tetrahydrofuran, dioxane.
8. the synthetic method stated according to claim 1, it is characterised in that the recrystallization reagent is selected from acetonitrile, water, methyl alcohol, second
The mixture of one or several any ratios in alcohol, tetrahydrofuran.
9. synthetic method according to claim 8, the recrystallization reagent is the mixture of acetonitrile and water, the acetonitrile with
The mol ratio of water is 8:1.
10. synthetic method according to claim 1, it is characterised in that be added dropwise after hydrolysing agent is added hydrochloric acid, sulfuric acid or
Person's acetic acid, and by pH value control between 3~6.
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Cited By (3)
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| CN109336801A (en) * | 2018-12-07 | 2019-02-15 | 无锡福祈制药有限公司 | A kind of doxercalciferol derivative and preparation method thereof |
| CN109369483A (en) * | 2018-12-07 | 2019-02-22 | 无锡福祈制药有限公司 | A kind of doxercalciferol analog and preparation method thereof |
| CN109456244A (en) * | 2018-12-12 | 2019-03-12 | 无锡福祈制药有限公司 | A kind of vitamine D3 class compound and preparation method thereof |
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| US6903083B2 (en) * | 2000-07-18 | 2005-06-07 | Bone Care International, Inc. | Stabilized hydroxyvitamin D |
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Cited By (3)
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| CN109336801A (en) * | 2018-12-07 | 2019-02-15 | 无锡福祈制药有限公司 | A kind of doxercalciferol derivative and preparation method thereof |
| CN109369483A (en) * | 2018-12-07 | 2019-02-22 | 无锡福祈制药有限公司 | A kind of doxercalciferol analog and preparation method thereof |
| CN109456244A (en) * | 2018-12-12 | 2019-03-12 | 无锡福祈制药有限公司 | A kind of vitamine D3 class compound and preparation method thereof |
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