CN109627279A - A kind of preparation method of activity of vitamin d3 intermediate - Google Patents
A kind of preparation method of activity of vitamin d3 intermediate Download PDFInfo
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Abstract
The present invention relates to a kind of preparation method of pharmaceutical intermediate, in particular to a kind of preparation method of 5,7,24- tri- enol of activity of vitamin d3 important intermediate cholesteric.It is using 25- hydroxyl -7-DHC as raw material, successively the following steps are included: the protection reaction of (1) derivatization: midbody compound II is made after raw material derivatization protection reaction；(2) midbody compound II is reacted using the D-A protection of diene is made intermediate compound III；(3) dehydration: intermediate compound IV is made by dehydration in intermediate compound III；(4) midbody compound IV finally passes through the activity of vitamin d3 intermediate that deprotection reaction is made required, i.e. cholesteric 5,7,24- tri- enols.Activity of vitamin d3 intermediate of the invention is 5,7,24- tri- enol of cholesteric with 24 double bond structures of side chain, so that the products material is easy to get by specific molecular modification method, high income, purity are good, preparation method simple and effective, has important application value.
Description
Technical field
The present invention relates to a kind of preparation method of pharmaceutical intermediate, in particular to a kind of activity of vitamin d3 important intermediate
The preparation method of tri- enol of cholesteric 5,7,24-.
Background technique
Vitamin D (vitamin D) is sterol analog derivative, has anti-rachitic effect, also known as antirachitic vitamin.
It is now recognized that vitamin D is also a kind of sterid.Wherein vitamine D3 and activity of vitamin d3 be vitamin D family at
Most important member in member.
Activity of vitamin d3 is the active metabolite of vitamine D3 in animal body, is had relative to vitamine D3 stronger
Activity.It is also widely used in feed addictive other than it can adjust internal alcium and phosphor metabolization, to promote poultry
Skeleton development.In addition, it is also adjustable immune function of human body, for treating osteoporosis, renal insufficiency, thyroid function
The skin diseases such as hyperfunction and psoriasis.In addition also very living in the research of the treatment and prevention field vitamine D3 class drug of cancer
Jump.Tri- enol of cholesteric 5,7,24- is a kind of intermediate of activity of vitamin d3.Before the present invention, vitamine D3 is among other
The preparation method of body is disclosed.Such as CN105669813B (2017-11-07) discloses a kind of intermediates of vitamin D_3 7- ketone
The synthetic method of cholesterol acetate, using cholesterol acetate as raw material carry out catalysis allylic oxidation reaction and etc. finally into
Row synthesis.Such as CN107098799A (2017-08-29) discloses a kind of system of activity of vitamin d3 class drug CD ring intermediate
Preparation Method, diol, derivatives specifically have passed through iodine substitution reaction, hydroxyl reaction, Michael addition reaction, nucleophilic addition, take off
Final activity of vitamin d3 class drug CD ring intermediate is made in protection reaction and oxidation reaction.But these methods are not suitable for living
The preparation of tri- enol of property intermediates of vitamin D_3 cholesteric 5,7,24-.
And cholesteric 5,7,24- tri- enols are because be difficult to synthesize and be rarely reported, or due to biological synthesis method itself
The problems such as limitation, the synthetic method is long there are reaction time, and concentration of substrate is low, and conversion ratio is low, and product purification is difficult, it is more difficult to carry out big
The industrial applications of scale.
Summary of the invention
A kind of be easy to get the object of the present invention is to provide raw material, high income, purity is good, simple and effective activity of vitamin d3
The preparation method of intermediate.
Above-mentioned technical purpose of the invention has the technical scheme that
A kind of preparation method of activity of vitamin d3 intermediate, with 25- hydroxyl -7-DHC shown in formula (I)
As raw material, successively the following steps are included:
(1) intermediate compound as shown in formula (II) derivatization protection reaction: is made after raw material derivatization protection reaction
Object II；
(2) D-A of diene protects reaction: midbody compound II is made using the D-A protection reaction of diene such as formula
(III) intermediate compound III shown in；
(3) dehydration: the intermediate compound as shown in formula (IV) is made by dehydration in intermediate compound III
IV；
(4) deprotection reaction: midbody compound IV finally passes through the activity of vitamin d3 that deprotection reaction is made required
Intermediate, i.e. 5,7,24- tri- enol of cholesteric as shown in formula (V)；
25- hydroxyl-the 7-DHC, midbody compound I, midbody compound II, midbody compound
The structural formula of III, midbody compound IV and tri- enol of cholesteric 5,7,24- is respectively such as formula (I), formula (II), formula (III), formula
(IV) and shown in formula (V):
Currently, the activity of vitamin d3 derivative main sides for having listed and being in clinical stage in the prior art focus on
The modification of A ring and side chain in cholesterol structure.Inventor the study found that the prior art is difficult to prepare high-purity cholesteric 5,7,
One major reason of tri- enol of 24- is possible to be that raw material selection is improper, and inventor selects from numerous existing substances
It selects, final choice 25- hydroxyl -7-DHC is as raw material.Activity of vitamin d3 of the invention is with side chain 24
5,7,24- tri- enol of cholesteric of double bond structure makes the products material be easy to get, is high income, pure by specific molecular modification method
It spends, preparation method simple and effective, there is important application value.
Preferably, step (1) the derivatization protection reaction includes:
Catalyst is made with DMAP as raw material using 25- hydroxyl -7-DHC shown in formula (I), in the work of acid binding agent
With it is lower with protection reagent temperature be -20 DEG C~80 DEG C at react, be made formula (II) shown in midbody compound II.
Derivatization protection reaction of the invention makees catalyst with acid binding agent, and acid binding agent is organic weak base, can prepare high receipts
The midbody compound II of rate, consequently facilitating the preparation of subsequent intermediate compound III, intermediate compound IV, to obtain high receipts
Tri- enol of cholesteric 5,7,24- of rate.
It is highly preferred that the acid binding agent in step 1) the derivatization protection reaction is triethylamine, pyridine, diethylamine, isopropyl
Amine, N, any one in N- diisopropylethylamine, triethanolamine, tetrabutylammonium bromide, DBU or DABCO；The acid binding agent with
25- hydroxyl -7-DHC molar ratio is 1.5~20:1.
It is highly preferred that above-mentioned steps 1) derivatization protection reaction in protection reagent be acetic anhydride, propionic andydride, butyric anhydride,
Benzoyl oxide, phthalic anhydride, 3,5- dinitrobenzoic acid acid anhydride, chloroacetic chloride, propionyl chloride, butyl chloride, chlorobenzoyl chloride or 3,5-
Any one in dinitrobenzoyl chloride；The protection reagent is with 25- hydroxyl -7-DHC molar ratio
1.0~6.0:1.
It is highly preferred that organic solvent used is acetone, butanone, cyclopentanone, ring in step 1) derivatization protection reaction
Hexanone, dimethylformamide, ethyl acetate, dimethyl sulfoxide, toluene, n-hexane, petroleum ether, ether, propyl ether, tetrahydrofuran, 1,
4- dioxane, methylene chloride, chloroform, any one or two kinds in carbon tetrachloride and two or more any ratios mixture；
The volumetric usage and 25- hydroxyl -7-DHC mass ratio of the step 1) organic solvent are 3~20ml/g.
Preferably, the D-A protection reaction of step (2) diene includes:
In organic solvent, midbody compound II and D-A the protection reagent triazoline compound that step 1) obtains are in temperature
Degree is the D-A protection reaction that diene is carried out at 0 DEG C~80 DEG C, and intermediate compound III shown in formula (III) is made.
The present invention carries out D-A protection reaction at a certain temperature, by being further made for midbody compound II high yield
Intermediate compound III, to be conducive to the progress of subsequent reactions.
It is highly preferred that D-A described in the D-A protection reaction of step (2) diene protects reagent triazoline compound
General structure it is as follows:
Wherein R is-Cl ,-Br ,-I ,-NO2、-OH、-COOH、-SO3And the alkyl under 4 carbon originals；
The D-A protection reagent and midbody compound II molar ratio are 1~2.0:1.
The present invention selects the triazoline compound of specific structure will be intermediate under specific molar ratio and above-mentioned specific temperature
Intermediate compound III is further made in body compound II high yield, to be conducive to the progress of subsequent reactions.
It is highly preferred that organic solvent used is methylene chloride, chloroform, second in the D-A protection reaction of step (2) diene
It is acetoacetic ester, acetone, glacial acetic acid, tetrahydrofuran, 1,4- dioxane, ether, propyl ether, toluene, n-hexane, any in petroleum ether
The mixture of one or two kinds of and two or more any ratios；
The volumetric usage of organic solvent in the D-A protection reaction of step (2) diene is with midbody compound II's
Mass ratio is 5~20ml/g.
The reaction of different phase is selected different organic solvents and is mutually matched, to be more advantageous to the organic of this stage
The organic reaction of reaction and follow-up phase, to improve the yield and purity of 5,7,24- tri- enol of final product cholesteric.
Preferably, step (3) dehydration includes:
In organic solvent, the intermediate compound III and dehydrated reagent that step 2) obtains are in the case where temperature is 0 DEG C~80 DEG C
Dehydration is carried out, midbody compound IV shown in formula (IV) is made；
Dehydrated reagent described in step (3) dehydration is phosphorus pentoxide, in p-methyl benzenesulfonic acid, acetic anhydride
Any one, the molar ratio of dehydrated reagent and intermediate III is 5~20:1.
Effective dehydration is carried out in the interaction of specific temperature, proportion and dehydrated reagent, to be more advantageous to
Subsequent deprotection reaction, so as to the cholesteric 5,7,24- tri- with 24 double bond structures of side chain of subsequent obtained high-purity
Enol.
It is highly preferred that in step (3) dehydration organic solvent used be benzene, it is toluene, any one in glacial acetic acid
The mixture of kind and two or more any ratios；The volumetric usage of organic solvent used and intermediate in step (3) dehydration
The quality of body compound III is 10~200ml/g.
The reaction of different phase is selected different organic solvents and is mutually matched, to be more advantageous to the organic of this stage
The organic reaction of reaction and follow-up phase, to improve the yield and purity of 5,7,24- tri- enol of final product cholesteric.
Preferably, step (4) deprotection reaction includes:
In organic solvent, the midbody compound IV and aluminium hydroborating reagent that step 3) obtains are 0 DEG C~120 DEG C in temperature
5,7,24- tri- enol of midbody compound V cholesteric shown in formula (V) is made in lower carry out deprotection reaction；The aluminium hydrogenates examination
Agent is Lithium Aluminium Hydride, three tertiary butyoxy aluminium lithiums, any one in diisobutyl aluminium hydride；The aluminium hydroborating reagent is in
Between compound IV molar ratio be 1~20:1.
The present invention need to only be carried out after dehydration a step deprotection reaction can be obtained high-purity have side chain 24
5,7,24- tri- enol of cholesteric of double bond structure, preparation method simple and effective have important application value.
It is highly preferred that organic solvent used is tetrahydrofuran in step (4) deprotection reaction；The step (4) is de-
The volumetric usage of organic solvent used and the quality of intermediate compound III are 10~200ml/g in protection reaction.
The reaction of different phase is selected different organic solvents and is mutually matched, to be more advantageous to the organic of this stage
The organic reaction of reaction and follow-up phase, to improve the yield and purity of 5,7,24- tri- enol of final product cholesteric.
In conclusion the invention has the following advantages: activity of vitamin d3 of the invention is double with side chain 24
5,7,24- tri- enol of cholesteric of bond structure, makes the products material be easy to get, high income, purity by specific molecular modification method
Good, preparation method simple and effective has important application value.
Specific embodiment
Technique of the invention is described further with embodiment below, but protection scope of the present invention is not by embodiment
Limitation.
Embodiment 1:
A kind of method preparing 5,7,24- tri- enol of cholesteric, comprising the following steps:
(1) derivatization is protected, and midbody compound II is made
Under room temperature (25 DEG C), 10.0g (24.96mmol) 25- hydroxyl -7-DHC is dissolved in 30ml n-hexane
In, addition, 4ml (42.32mmol) acetic anhydride and 10mmol pyridine are stirred to react 5.0h at 45 DEG C, and TLC tracks fully reacting
Afterwards, water 20ml washing layering is added to remove water phase, organic phase washs layering with 10% dilute hydrochloric acid of 10ml and removes water phase, and organic phase is right
It is washed afterwards with 10ml deionized water and is layered removal water phase, after last organic phase concentration and recovery n-hexane, 50ml methanol, dissolution is added
Afterwards, decrease temperature crystalline filters to obtain 11.05g midbody compound II, yield 100.0%.
(2) diene is protected, and intermediate compound III is made
1.15g (2.60mmol) midbody compound II is dissolved in 30ml methylene chloride, 0.49g is added portionwise
(2.80mmol) 4- phenyl -1,2,4- triazoline -3,5- diketone are stirred to react 0.5h at 25 DEG C, after TLC tracks fully reacting,
Recycling removal methylene chloride, filters to obtain 1.55g (2.52mmol) intermediate compound III, yield after ether stirring is then added
96.9%, 161.5-162.5 DEG C of fusing point.
1H NMR(CDCL3)δ7.36(m,5H),6.40(d,1H),6.22(d,1H),5.44(m,1H),5.07(t,1H),
3.22(dd,1H),2.01(s,3H),1.68(s,3H),1.59(s,3H),0.99(s,3H),0.95(d,3H),0.80(s,
3H)。
(3) midbody compound IV is made in dehydration
1.5g (2.44mmol) intermediate compound III is dissolved in 200ml benzene, 5g is added in batches at 25 DEG C
(35.23mmol) phosphorus pentoxide, is stirred to react 1.5h at 35 DEG C, TLC track dehydration it is complete after, reaction solution is added to
In 100ml cold saturated sodium bicarbonate aqueous solution, layering removal water phase, organic phase is washed three times using 100ml deionized water, point
After layer removal water phase, organic phase is dry with the dry post-tensioning of anhydrous sodium sulfate, and column chromatography for separation obtains 1.37g (2.29mmol) intermediate
Close object IV, yield 94.1%.
(4) final product V is made in deprotection reaction
1.0g (1.67mmol) midbody compound IV is dissolved in the dry tetrahydrofuran of 100ml, stirring and dissolving, 0 DEG C
Lower addition 1.8g (47.43mmol) Lithium Aluminium Hydride, after stirring 0.5h, temperature rising reflux reacts 1.5h, after TLC tracks fully reacting,
Reaction solution is added dropwise and is entered in 100ml10% dilute hydrochloric acid solution, the imitative extraction of chlorination.Organic layer saturated sodium bicarbonate and saturation chlorine
After changing sodium solution washing, it will be concentrated after organic layer anhydrous sodium sulfate drying, column chromatography for separation obtains 0.62g activity of vitamin d3
5,7,24- tri- enol of important intermediate, that is, final product cholesteric, yield 96.9%, HPLC purity 99.36% (280nm), fusing point
104℃-107℃。
1H NMR(CDCl3) δ 5.56 (m, 1H), 5.38 (m, 1H), 5.08 (t, 1H), 3.63 (m, 1H), 1.68 (s, 3H),
1.60 (s, 3H), 0.96 (d, 3H), 0.94 (s, 3H), 0.62 (s, 3H).
Embodiment 2:
With embodiment 1, the difference is that step (1) reaction are as follows:
Using 25- hydroxyl -7-DHC shown in formula (I) as raw material, under the action of acid binding agent with protection reagent
It is reacted at being -20 DEG C in temperature, midbody compound II shown in formula (II) is made；Midbody compound II yield is
96.2%.Final product yield is 96.7%, cholesteric 5,7, tri- enol HPLC purity 99.52% (280nm) of 24-.
Wherein,.Acid binding agent is triethylamine and 25- hydroxyl -7-DHC molar ratio is 1.5:1.
Protection reagent in step 1) is propionic andydride；Protect reagent and 25- hydroxyl -7-DHC molar ratio
For 1.0:1.
Organic solvent used is the acetone and butanone of volume ratio 1:1 mixing composition in step 1)；Step 1) organic solvent
Volumetric usage and 25- hydroxyl -7-DHC mass ratio are 3ml/g.
Embodiment 3:
With embodiment 1, the difference is that step (1) reaction are as follows:
Using 25- hydroxyl -7-DHC shown in formula (I) as raw material, under the action of acid binding agent with protection reagent
It is reacted at being 80 DEG C in temperature, midbody compound II shown in formula (II) is made.Tri- enol of final product cholesteric 5,7,24- is received
Rate is 95.2%, HPLC purity 99.61% (280nm).
Wherein.Acid binding agent is triethylamine, pyridine, diethylamine, isopropylamine, N, N- diisopropylethylamine, triethanolamine, four fourths
Any one in base ammonium bromide, DBU or DABCO；Acid binding agent and 25- hydroxyl -7-DHC molar ratio are 20:
1。
Protection reagent in step 1) is benzoyl oxide；Protection reagent and 25- hydroxyl -7-DHC feed intake mole
Than for 6.0:1.
Organic solvent used is dimethylformamide, volumetric usage and 25- hydroxyl -7-DHC matter in step 1)
Amount is than being 20ml/g.
Embodiment 4:
With embodiment 1, the difference is that step (2) reaction are as follows:
In organic solvent, midbody compound II and D-A the protection reagent triazoline compound that step 1) obtains are in temperature
Degree is the D-A protection reaction that diene is carried out at 0 DEG C, and intermediate compound III shown in formula (III) is made.Midbody compound
III yield is 94.1%.5,7,24- tri- enol yield of final product cholesteric is 97.3%, HPLC purity 99.13% (280nm).
Wherein, D-A described in step (2) protects the general structure of reagent triazoline compound as follows:
Wherein R is-Cl；
D-A protects reagent and midbody compound II molar ratio is 1:1.
Organic solvent used is the ethyl acetate that 1:3 is mixed by volume in the D-A protection reaction of step (2) diene
And acetone；
The volumetric usage of organic solvent in step (2) and the mass ratio of midbody compound II are 5ml/g.
Embodiment 5:
With embodiment 1, the difference is that step (2) reaction are as follows:
In organic solvent, midbody compound II and D-A the protection reagent triazoline compound that step 1) obtains are in temperature
Degree is the D-A protection reaction that diene is carried out at 80 DEG C, and intermediate compound III shown in formula (III) is made.Midbody compound
III yield is 93.6%.5,7,24- tri- enol yield of final product cholesteric is 98.37%, HPLC purity 99.37%
(280nm)。
Wherein, D-A protects the general structure of reagent triazoline compound as follows in step (2):
Wherein R is the alkyl under 4 carbon originals；
D-A protects reagent and midbody compound II molar ratio is 2.0:1.
Organic solvent used is Isosorbide-5-Nitrae-dioxane, volumetric usage and intermediate in the D-A protection reaction of step (2) diene
The mass ratio of compound II is 20ml/g.
Embodiment 6:
With embodiment 1, the difference is that step (3) reaction are as follows:
In organic solvent, the intermediate compound III and dehydrated reagent that step 2) obtains are taken off at being 0 DEG C in temperature
Water reaction, is made midbody compound IV shown in formula (IV)；Midbody compound IV yield is 94.6%.Final product cholesteric
5,7,24- tri- enol yields are 98.89%, HPLC purity 98.88% (280nm).
Wherein, dehydrated reagent described in step (3) is p-methyl benzenesulfonic acid, the molar ratio of dehydrated reagent and intermediate III
For 5:1；
Organic solvent used is the mixture of 2:1 is mixed by volume benzene and toluene in step (3) dehydration；
The quality of the volumetric usage and intermediate compound III of organic solvent used is 10ml/g in step (3) dehydration.
Embodiment 7:
With embodiment 1, the difference is that step (3) reaction are as follows:
In organic solvent, the intermediate compound III and dehydrated reagent that step 2) obtains carry out at being 80 DEG C in temperature
Midbody compound IV shown in formula (IV) is made in dehydration；Midbody compound IV yield is 95.1%.Final product gallbladder
Steroid 5,7, tri- enol yield of 24- are 98.53%, HPLC purity 99.37% (280nm).
Wherein, dehydrated reagent described in step (3) is acetic anhydride, and the molar ratio of dehydrated reagent and intermediate III is 20:
1；
Organic solvent used is the mixture of toluene and glacial acetic acid that 1:3 is mixed in step (3) dehydration；It is described
The quality of the volumetric usage and intermediate compound III of organic solvent used is 200ml/g in step (3) dehydration.
Embodiment 8:
With embodiment 1, the difference is that step (4) reaction are as follows:
In organic solvent, the midbody compound IV that step 3) obtains and aluminium hydroborating reagent carry out at being 0 DEG C in temperature
Deprotection reaction, is made 5,7,24- tri- enol of cholesteric shown in formula (V), and 5,7,24- tri- enol yield of final product cholesteric is
98.9%；HPLC purity 99.46% (280nm).
Wherein, aluminium hydroborating reagent is three tertiary butyoxy aluminium lithiums, and the molar ratio with intermediate compound IV is 1:1；Step
(4) organic solvent used is the volumetric usage of tetrahydrofuran in and the quality of intermediate compound III is 10ml/g.
Embodiment 9:
With embodiment 1, the difference is that step (4) reaction are as follows:
In organic solvent, step 3) obtains midbody compound IV and aluminium hydroborating reagent be 120 DEG C in temperature at into
Row deprotection reaction, is made 5,7,24- tri- enol of cholesteric shown in formula (V), and final product yield is 99.1%；HPLC purity
99.29% (280nm).
Wherein, aluminium hydroborating reagent is diisobutyl aluminium hydride, and the molar ratio with intermediate compound IV is 20:1；Step (4)
In organic solvent used be the quality of tetrahydrofuran and intermediate compound III be 200ml/g.
Comparative example 1:
With embodiment 1, the difference is that step (1) is reacted at being 100 DEG C in temperature, with the selection of step (1) same composition
Acid binding agent, protection reagent and 25- hydroxyl -7-DHC molar ratio are 0.3:0.5:8.0:1.The body of organic solvent
Product dosage and 25- hydroxyl -7-DHC mass ratio are 1ml/g.Remaining step is the same as embodiment 1.Obtain intermediate compound
Object II yield is 80.5%, and 5,7,24- tri- enol yield of final product cholesteric is 60.4%, HPLC purity 75.37%
(280nm)。
Comparative example 2:
With embodiment 1, the difference is that step (2) carries out diene D-A at being 120 DEG C in temperature is protected and is reacted, in reaction
Organic solvent volumetric usage and midbody compound II mass ratio be 30ml/g.Intermediate compound III yield is
76.5%.5,7,24- tri- enol yield of final product cholesteric is 52.1%, HPLC purity 71.36% (280nm).
Comparative example 3:
It is made shown in formula (IV) with embodiment 1 the difference is that step (3) carries out dehydration at being 90 DEG C in temperature
Midbody compound IV；The molar ratio of dehydrated reagent and intermediate III is 3:1.Organic solvent used is tetrahydro in dehydration
Furans；The volumetric usage of tetrahydrofuran and the quality of intermediate compound III are 5ml/g.Midbody compound IV yield is
63.1%.5,7,24- tri- enol yield of final product cholesteric is 40.5%, HPLC purity 82.44% (280nm).
Comparative example 4:
It is made shown in formula (V) with embodiment 1 the difference is that step (4) carries out deprotection reaction at being 140 DEG C in temperature
Tri- enol of midbody compound V cholesteric 5,7,24-；The aluminium hydroborating reagent is sodium alanate, with intermediate compound IV's
Molar ratio is 10:1.
Organic solvent used is toluene, the volumetric usage and intermediate compound III of toluene in step (4) deprotection reaction
Quality be 100ml/g.5,7,24- tri- enol product yield of final product cholesteric is 51.4%, HPLC purity 80.14%
(280nm)。
Comparative example 5:
It is made shown in formula (V) with embodiment 1 the difference is that step (4) carries out deprotection reaction at being 140 DEG C in temperature
Tri- enol of midbody compound V cholesteric 5,7,24-；Aluminium hydroborating reagent is sodium alanate, the molar ratio with intermediate compound IV
For 30:1.
Organic solvent used is tetrahydrofuran, the volumetric usage and intermediate of tetrahydrofuran in step (4) deprotection reaction
The quality of compound III is 5ml/g.5,7,24- tri- enol product yield of final product cholesteric is 66.9%, HPLC purity
74.29% (280nm).
Comparative example 6:
With embodiment 1, the difference is that step (1) is reacted at being 100 DEG C in temperature, acid binding agent, protection reagent and 25- hydroxyl
Base -7-DHC molar ratio is 0.3:0.5:8.0:1.The volumetric usage and 25- hydroxyl -7- dehydrogenation of organic solvent
The mass ratio of cholesterol is 1ml/g.Step (3) carries out dehydration at being 90 DEG C in temperature, is made intermediate shown in formula (IV)
Body compound IV；The molar ratio of dehydrated reagent and intermediate III is 3:1.Organic solvent used is tetrahydrofuran in dehydration；
The volumetric usage of tetrahydrofuran and the quality of intermediate compound III are 5ml/g.Midbody compound IV yield is 24.6%.
Tri- enol HPLC purity 56.24% (280nm) of final product cholesteric 5,7,24-.
Comparative example 7:
With embodiment 1, the difference is that step (1) is reacted at being 100 DEG C in temperature, acid binding agent, protection reagent and 25- hydroxyl
Base -7-DHC molar ratio is 0.3:0.5:8.0:1.The volumetric usage and 25- hydroxyl -7- dehydrogenation of organic solvent
The mass ratio of cholesterol is 1ml/g.Step (2) carries out diene D-A at being 120 DEG C in temperature protects reaction, having in reaction
The volumetric usage of solvent and the mass ratio of midbody compound II are 30ml/g.Intermediate compound III yield is 21.5%.
5,7,24- tri- enol yield of final product cholesteric is 35.63%, HPLC purity 56.35% (280nm).
Comparative example 8
With embodiment 1, the difference is that step (2) carries out diene D-A at being 120 DEG C in temperature is protected and is reacted, in reaction
Organic solvent volumetric usage and midbody compound II mass ratio be 30ml/g.Step (3) temperature be 90 DEG C at into
Midbody compound IV shown in formula (IV) is made in row dehydration；The molar ratio of dehydrated reagent and intermediate III is 3:1.It is de-
Organic solvent used is tetrahydrofuran in water reaction；The volumetric usage of tetrahydrofuran and the quality of intermediate compound III are
5ml/g.Midbody compound IV yield is 26.5%.5,7,24- tri- enol yield of final product cholesteric is 28.53%, HPLC
Purity 43.68% (280nm).
Comparative example 9
With embodiment 1, the difference is that step (1) is reacted at being 100 DEG C in temperature, acid binding agent, protection reagent and 25- hydroxyl
Base -7-DHC molar ratio is 0.3:0.5:8.0:1.The volumetric usage and 25- hydroxyl -7- dehydrogenation of organic solvent
The mass ratio of cholesterol is 1ml/g.Step (4) carries out deprotection reaction at being 140 DEG C in temperature, is made in shown in formula (V)
Tri- enol of intermediate compounds therefor V cholesteric 5,7,24-；The aluminium hydroborating reagent is sodium alanate, mole with intermediate compound IV
Than for 10:1.Organic solvent used is toluene, the volumetric usage and midbody compound of toluene in step (4) deprotection reaction
The quality of III is 100ml/g.Tri- enol product yield of final product cholesteric 5,7,24- is 13.4%, HPLC purity 24.56%
(280nm)。
From embodiment and comparative example it can be seen that
1. the yield that embodiment 1-9 can be seen that 5,7,24- tri- enol of activity of vitamin d3 intermediate cholesteric of the present invention is
95.2%-99.1%, yield are higher；Purity is 98.88-99.36%, purity is high；And 9 yield of comparative example is minimum only
13.4%, purity only has 24.56%；
2. embodiment 1-9 and comparative example 1-5 compare the original as can be seen that each step in four steps of the invention
Material selection and formula all have an impact to each intermediate yield therein and purity, to influence in final product activity of vitamin d3
The yield and purity of tri- enol of mesosome cholesteric 5,7,24-；
3. comparative example 1-5 and comparative example 6-9 compare as can be seen that when more than two steps therein are all different
When the present invention, yield and the purity decline of product are bigger.Illustrate the mutual selection combination of each step and reacts to of the invention
The yield and impurities affect of tri- enol of final product activity of vitamin d3 intermediate cholesteric 5,7,24- are bigger.
This specific embodiment is only explanation of the invention, is not limitation of the present invention, those skilled in the art
Member can according to need the modification that not creative contribution is made to the present embodiment after reading this specification, but as long as at this
All by the protection of Patent Law in the scope of the claims of invention.
Claims (10)
1. a kind of preparation method of activity of vitamin d3 intermediate, it is characterised in that: it is gone with 25- hydroxyl -7- shown in formula (I)
Hydrogen cholesterol as raw material, successively the following steps are included:
(1) the midbody compound II as shown in formula (II) derivatization protection reaction: is made after raw material derivatization protection reaction；
(2) D-A of diene protects reaction: midbody compound II is made as shown in formula (III) by the D-A protection reaction of diene
Intermediate compound III；
(3) dehydration: the intermediate compound IV as shown in formula (IV) is made by dehydration in intermediate compound III；
(4) deprotection reaction: midbody compound IV finally passes through among the activity of vitamin d3 that deprotection reaction is made required
Body, i.e. 5,7,24- tri- enol of cholesteric as shown in formula (V)；
25- hydroxyl-the 7-DHC, midbody compound I, midbody compound II, intermediate compound III, in
The structural formula of tri- enol of intermediate compounds therefor IV and cholesteric 5,7,24- is respectively such as formula (I), formula (II), formula (III), formula (IV) and formula
(V) shown in:
2. a kind of preparation method of activity of vitamin d3 intermediate according to claim 1, it is characterised in that: the step
(1) derivatization protection, which is reacted, includes:
Catalyst is made with acid binding agent as raw material using 25- hydroxyl -7-DHC shown in formula (I), in the effect of acid binding agent
It is reacted at being down -20 DEG C~80 DEG C in temperature with protection reagent, midbody compound II shown in formula (II) is made.
3. a kind of preparation method of activity of vitamin d3 intermediate according to claim 2, it is characterised in that: the step
1) acid binding agent in derivatization protection reaction is triethylamine, pyridine, diethylamine, isopropylamine, N, N- diisopropylethylamine, three ethyl alcohol
Any one in amine, tetrabutylammonium bromide, DBU or DABCO；
The acid binding agent and 25- hydroxyl -7-DHC molar ratio are 1.5~20:1.
4. a kind of preparation method of activity of vitamin d3 intermediate according to claim 3, it is characterised in that: step 1) is spread out
Protection reagent in biochemistry protection reaction is acetic anhydride, propionic andydride, butyric anhydride, benzoyl oxide, phthalic anhydride, 3,5- dinitro
Yl benzoic acid acid anhydride, chloroacetic chloride, propionyl chloride, butyl chloride, chlorobenzoyl chloride or 3, any one in 5- dinitrobenzoyl chloride；
The protection reagent and 25- hydroxyl -7-DHC molar ratio are 1.0~6.0:1.
5. a kind of preparation method of activity of vitamin d3 intermediate according to claim 1, it is characterised in that: step (2)
The D-A protection of diene, which is reacted, includes:
In organic solvent, midbody compound II and D-A the protection reagent triazoline compound that step 1) obtains are 0 in temperature
DEG C~80 DEG C at carry out diene D-A protect reaction, be made formula (III) shown in intermediate compound III.
6. a kind of preparation method of activity of vitamin d3 intermediate according to claim 5, it is characterised in that: step (2)
The general structure of D-A protection reagent triazoline compound described in the D-A protection reaction of diene is as follows:
Wherein R is the alkyl under-Cl ,-Br ,-I ,-NO2 ,-OH ,-COOH ,-SO3 and 4 carbon original；
The D-A protection reagent and midbody compound II molar ratio are 1~2.0:1.
7. a kind of preparation method of activity of vitamin d3 intermediate according to claim 1, it is characterised in that: the step
(3) dehydration includes:
In organic solvent, the intermediate compound III and dehydrated reagent that step 2) obtains carry out at being 0 DEG C~80 DEG C in temperature
Midbody compound IV shown in formula (IV) is made in dehydration；
Dehydrated reagent described in step (3) dehydration is phosphorus pentoxide, p-methyl benzenesulfonic acid, any in acetic anhydride
The molar ratio of one kind, dehydrated reagent and intermediate III is 5~20:1.
8. a kind of preparation method of activity of vitamin d3 intermediate according to claim 7, it is characterised in that: the step
(3) in dehydration organic solvent used be benzene, toluene, any one and two or more any ratios in glacial acetic acid mixing
Object；In step (3) dehydration quality of the volumetric usage and intermediate compound III of organic solvent used be 10~
200ml/g。
9. a kind of preparation method of activity of vitamin d3 intermediate according to claim 1, it is characterised in that: the step
(4) deprotection reaction includes:
In organic solvent, step 3) obtains midbody compound IV and aluminium hydroborating reagent be 0 DEG C~120 DEG C in temperature at into
5,7,24- tri- enol of midbody compound V cholesteric shown in formula (V) is made in row deprotection reaction；The aluminium hydroborating reagent is
Lithium Aluminium Hydride, three tertiary butyoxy aluminium lithiums, any one in diisobutyl aluminium hydride；The aluminium hydroborating reagent and centreization
The molar ratio for closing object IV is 1~20:1.
10. a kind of preparation method of activity of vitamin d3 intermediate according to claim 9, it is characterised in that: the step
Suddenly organic solvent used is tetrahydrofuran in (4) deprotection reaction；Organic solvent used in step (4) deprotection reaction
The quality of volumetric usage and intermediate compound III is 10~200ml/g.
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| CN111892637A (en) * | 2020-07-16 | 2020-11-06 | 山东海能生物工程有限公司 | Preparation method of 7-dehydro-25-hydroxycholesterol |
| CN113004367A (en) * | 2019-12-19 | 2021-06-22 | 帝斯曼知识产权资产管理有限公司 | Diels-alder adducts and derivatives |
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