CN104910231B - A kind of synthetic method of 25-hydroxyl-7-DHC - Google Patents
A kind of synthetic method of 25-hydroxyl-7-DHC Download PDFInfo
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Abstract
The present invention relates to the synthetic method of a kind of 25 hydroxyl 7 dehydrocholesterols.It is with 25 hydroxyl 7 ketone group cholesterol derivatives as raw material, under sulfohydrazide and alkali effect, under organic solvent-free, and mechanical ball milling reaction in ball grinder, then obtain 25 hydroxyl 7 dehydrocholesterols through hydrolysis.The present invention, under condition of no solvent, uses mechanical ball milling reaction, and its attrition process is without there being flour dust overflow, and reaction controllability is good, and reaction efficiency is high, and avoids in post processing the reclaimer operation to solvent, simplifies operation, reduces environmental pollution, environmental protection；And good reaction selectivity, yield is high, easy and simple to handle, low cost, and post processing is simple, and the three wastes are few, and product is easily separated and purity is high, and its yield is up to 89%, and melting range is short, and product purity is high.
Description
Technical field
The present invention relates to the synthetic method of a kind of 25-hydroxyl-7-DHC.
Background technology
25-hydroxyl-7-DHC has another name called 25-hydroxy-vitamin D3Former, irradiate through ultraviolet light and can synthesize 25-hydroxyl dimension
Raw element D3, 25-hydroxy-vitamin D3Have another name called calcifediol, be vitamin D3The active metabolite of internal liver, has higher life
Reason activity, can have been widely used for animal farming industry at present as feed additive.
25-hydroxy-vitamin D3Market is the best, at present in the animal husbandry large-scale use in Europe, therefore in key
Mesosome 25-hydroxyl-7-DHC market potential is the biggest.Before making the present invention, 25-hydroxyl-7-DHC is general
With 25-HYDROXY CHOLESTEROL derivant as raw material, it is prepared through bromo-debromination.Following (the Journal of of reaction equation
Organic Chemistry, 2005, 70(21), 8513-8521; Tetrahedron Letters, 2004, 45
(40), 7479-7482),
,
In said method, brominated reagent is generally bromine, NBS, DBDMH etc., and not only consumption is big and corrosivity serious,
Being unfavorable for operation, quantity of three wastes is big and difficult.It addition, the method also creates a kind of difficult impurity removed, to follow-up photochemical instead
Should affect huge, be unfavorable for large-scale industrial production.After deliberation, we have invented a kind of synthesis 5 being beneficial to industrialization,
The method (patent No. ZL 200810121443.0) of 7-diene steroids compounds, the method has had for traditional method and has changed the most greatly
Enter.But finding still to have bigger room for improvement through follow-up study, the method uses low temperature (-20 DEG C), basic conditions, and raw material is
Sulphonyl hydrazone unstable in air and water, sulphonyl hydrazone typically by 7-ketone group steroid and sulfohydrazide reaction preparation, needs
Purification to be separated, step is the most cumbersome.Therefore, exploitation is a kind of efficiently on this basis, one kettle way, environmental protection and easily realize industrialization
25-hydroxyl-7-DHC synthetic method, there is higher economic and social benefit.
Summary of the invention
For the above-mentioned problems in the prior art, it is an object of the invention to provide efficiently, one kettle way, environmental protection and easily
Realize the synthetic method of the 25-hydroxyl-7-DHC of industrialization.
The technical solution used in the present invention is:
25-hydroxyl-7-DHC synthetic method shown in a kind of formula (I), it is characterised in that described method is: with
25-hydroxyl-7-ketone group cholesterol derivative shown in formula (II) is raw material, under the sulfohydrazide shown in formula (III) and alkali effect,
Under organic solvent-free, react at mechanical ball milling, then obtain the 25-hydroxyl-7-DHC shown in formula (I) through hydrolysis, described
25-hydroxyl-7-DHC, 25-hydroxyl-7-ketone group cholesterol derivative and sulfohydrazide structural formula respectively as formula (I),
Shown in formula (II), formula (III):
,
Wherein: R1For the acyl group of C1～C12, or C1～C12 sulfonyl；R2For the acyl group of C1～C12, or C1～C12 sulphonyl
Base；R3For methyl or phenyl or p-methylphenyl.
Alkali is one of following: lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, Lithium hydrate, sodium hydroxide, potassium hydroxide,
Cesium hydrate., Feldalat NM, Sodium ethylate, potassium tert-butoxide, lithium hydride, sodium hydride, Lithamide., Sodamide..
The ball-milling reaction time is 0.1～5 hour, preferably 0.5～1 hour, and hydrolysis agents useful for same is sodium hydroxide or hydrogen
Potassium oxide, hydrolysising reacting temperature is 40～80 DEG C, and the time is 1～2 hour, and hydrolysis pH value controls >=13.
Sulfohydrazide shown in 25-hydroxyl-7-ketone group cholesterol derivative shown in formula (II), formula (III), the mol ratio of alkali
For 1:1～5:1～10, preferred molar ratio is 1:1～2:1～2.
The synthetic method of the present invention is carried out in accordance with the following steps: spread out by the 25-hydroxyl-7-ketone group cholesterol shown in formula (II)
Sulfohydrazide shown in biological, formula (III), alkali join in ball grinder ball-milling reaction 0.1～5 hours, after reaction completely, water washed
Filter, joins filter cake in ethanol and dissolves, and adds sodium hydroxide or potassium hydroxide, controls pH value >=13, anti-at 40～80 DEG C
Answer 1～2 hour, be down to crystallizing at room temperature, filter, obtain faint yellow solid, then obtain white flaky crystals 25-through ethyl alcohol recrystallization
Hydroxyl-7-DHC.The reaction equation of the present invention is as follows:
By using above-mentioned technology, compared with prior art, the beneficial effects of the present invention is:
1) agents useful for same of the present invention is environmentally friendly, it is to avoid the bromine that environmental pollution is serious, corrosivity is strong, NBS etc.
Use；
2) present invention is under condition of no solvent, uses mechanical ball milling reaction, and its attrition process is without there being flour dust overflow, and reaction can
Control property is good, and reaction efficiency is high, and avoids in post processing the reclaimer operation to solvent, simplifies operation, reduces environment dirty
Dye, environmental protection；
3) good reaction selectivity of the present invention, yield is high, easy and simple to handle, low cost, and post processing is simple, and the three wastes are few, produce
Product are easily separated and purity is high, and its yield is up to 89%, and melting range is short, and product purity is high.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is described further, but protection scope of the present invention is not limited in
This:
Embodiment 1:
At room temperature, by 5.0g(10 mmol) 25-hydroxyl-7-ketone group cholesterol diacetate (R1=R2=Ac), 2.05g
(11 mmol) unifor, 1.19g(22 mmol) Feldalat NM is added sequentially in ball grinder, ball-milling reaction 0.5 hour,
After reaction terminates, reactant mixture 20mL water washing and filtering, filter cake is joined in 25mL ethanol (95%) and dissolve, add hydrogen
Sodium oxide, controls pH value >=13, reacts 1 hour at 50 DEG C, is down to crystallizing at room temperature, filters, obtains faint yellow solid, then through ethanol
It is recrystallized to give white flaky crystals, 25-hydroxyl-7-DHC 3.52g, yield 88%, fusing point 191 ~ 193 DEG C,1H NMR
(400 MHz, CDCl3) δ = 5.55 - 5.57 (m, 1H), 5.36 - 5.39 (m, 1H), 3.59-3.67 (m,
1H), 2.44 – 2.49 (m, 1H), 2.25 - 2.31(m, 1H), 2.06 - 2.11(m, 1H), 1.87 - 1.99
(m, 4H), 1.54 - 1.75 (m, 7H), 1.26 - 1.51 (m, 11H), 1.22 (s, 6H), 1.02 - 1.10
(m, 1H), 0.95 (s, 4H), 0.60 (s, 3H). MS(ESI): m/z (%) = 423.2 (M++Na)。
Embodiment 2:
At room temperature, by 5.0g(10 mmol) 25-hydroxyl-7-ketone group cholesterol diacetate (R1=R2=Ac), 2.05g
(11 mmol) unifor, 0.18g(22 mmol) lithium hydride is added sequentially in ball grinder, ball-milling reaction 0.5 hour,
After reaction terminates, reactant mixture 20mL water washing and filtering, filter cake is joined in 25mL ethanol (95%) and dissolve, add hydrogen
Sodium oxide, controls pH value >=13, reacts 1 hour at 50 DEG C, is down to crystallizing at room temperature, filters, obtains faint yellow solid, then through ethanol
It is recrystallized to give white flaky crystals, 25-hydroxyl-7-DHC 3.48g, yield 87%, fusing point 191 ~ 193 DEG C.
Embodiment 3:
At room temperature, by 5.0 g(10 mmol) 25-hydroxyl-7-ketone group cholesterol diacetate (R1=R2=Ac), 2.05g
(11 mmol) unifor, 0.86g(22 mmol) Sodamide. is added sequentially in ball grinder, ball-milling reaction 0.5 hour,
After reaction terminates, reactant mixture 20mL water washing and filtering, filter cake is joined in 25mL ethanol (95%) and dissolve, add hydrogen
Sodium oxide, controls pH value >=13, reacts 1 hour at 50 DEG C, is down to crystallizing at room temperature, filters, obtains faint yellow solid, then through ethanol
It is recrystallized to give white flaky crystals, 25-hydroxyl-7-DHC 3.56g, yield 89%, fusing point 191 ~ 193 DEG C.
Embodiment 4:
At room temperature, by 5.0g(10 mmol) 25-hydroxyl-7-ketone group cholesterol diacetate (R1=R2=Ac), 1.89g
(11 mmol) benzene sulfonyl hydrazide, 1.23g(22 mmol) potassium hydroxide is added sequentially in ball grinder, ball-milling reaction 2 hours, reaction
After end, reactant mixture 20mL water washing and filtering, filter cake is joined in 25mL ethanol (95%) and dissolve, add hydroxide
Sodium, controls pH value >=13, reacts 1 hour at 50 DEG C, is down to crystallizing at room temperature, filters, obtains faint yellow solid, more heavily tie through ethanol
Crystalline substance obtains white flaky crystals, 25-hydroxyl-7-DHC 2.84g, yield 71%, fusing point 190 ~ 192 DEG C.
Embodiment 5:
At room temperature, by 5.0g(10 mmol) 25-hydroxyl-7-ketone group cholesterol diacetate (R1=R2=Ac), 1.21g
(11 mmol) methylsulfonyl hydrazine, 7.17g(22 mmol) cesium carbonate is added sequentially in ball grinder, ball-milling reaction 2 hours, reaction knot
Shu Hou, reactant mixture 20mL water washing and filtering, filter cake is joined in 25mL ethanol (95%) and dissolve, add sodium hydroxide,
Control pH value >=13, react 1 hour at 50 DEG C, be down to crystallizing at room temperature, filter, obtain faint yellow solid, then through ethyl alcohol recrystallization
Obtain white flaky crystals, 25-hydroxyl-7-DHC 1.84g, yield 46%, fusing point 190 ~ 192 DEG C.
Embodiment 6:
Raw material becomes 25-hydroxyl-7-ketone group cholesterol dibenzoate (R1=R2=Bz, 10 mmol), other operations are with real
Execute example 1, obtain 25-hydroxyl-7-DHC 3.36g, yield 84%.
Embodiment 7:
Raw material becomes 25-hydroxyl-7-ketone group cholesterol two p-toluenesulfonic esters (R1=R2=Ts, 10 mmol), other operations
With embodiment 1, obtain 25-hydroxyl-7-DHC 3.24g, yield 81%.
Embodiment 8:
The ball-milling reaction time becomes 0.1 hour, and other operations, with embodiment 1, obtain 25-hydroxyl-7-DHC
2.76g, yield 69%.
Embodiment 9:
The ball-milling reaction time becomes 5 hours, and other operations, with embodiment 1, obtain 25-hydroxyl-7-DHC
2.92g, yield 73%.
Claims (6)
1. the synthetic method of 25-hydroxyl-7-DHC, it is characterised in that described method is: with such as formula (II) institute
25-hydroxyl-7-ketone group the cholesterol derivative shown is raw material, under sulfohydrazide as shown in the formula (III) and alkali effect, without organic
Under solvent, ball grinder carries out mechanical ball milling reaction, then obtains 25-hydroxyl-7-dehydrogenation as shown in the formula (I) through hydrolysis
Cholesterol, the ball-milling reaction time is 0.1～5 hour, and hydrolysising reacting temperature is 40～80 DEG C, and the time is 1～2 hour, and hydrolysis is anti-
Answer pH value to control >=13,25-hydroxyl-7-ketone group cholesterol derivative, sulfohydrazide, the molar ratio of alkali be 1:1～5:1～
10；The structural formula of 25-hydroxyl-7-DHC, 25-hydroxyl-7-ketone group cholesterol derivative and sulfohydrazide is respectively such as formula
(I), shown in formula (II), formula (III):
,
In formula, R1For the acyl group of C1～C12, or the sulfonyl of C1～C12；R2For the acyl group of C1～C12, or the sulphonyl of C1～C12
Base；R3For methyl or phenyl or p-methylphenyl.
The synthetic method of a kind of 25-hydroxyl-7-DHC the most as claimed in claim 1, it is characterised in that described alkali
It is selected from: lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, Lithium hydrate, sodium hydroxide, potassium hydroxide, Cesium hydrate., Feldalat NM,
Sodium ethylate, potassium tert-butoxide, lithium hydride, sodium hydride, Lithamide., Sodamide..
The synthetic method of a kind of 25-hydroxyl-7-DHC the most as claimed in claim 1, its feature ball-milling reaction time
It it is 0.5～1 hour.
The synthetic method of a kind of 25-hydroxyl-7-DHC the most as claimed in claim 1, it is characterised in that hydrolysis
Agents useful for same is sodium hydroxide or potassium hydroxide.
The synthetic method of a kind of 25-hydroxyl-7-DHC the most as claimed in claim 1, it is characterised in that 25-hydroxyl-
7-ketone group cholesterol derivative, sulfohydrazide, the molar ratio of alkali are 1:1～2:1～2.
The synthetic method of a kind of 25-hydroxyl-7-DHC the most as claimed in claim 1, it is characterised in that according to as follows
Step is carried out: the sulfohydrazide shown in the 25-hydroxyl-7-ketone group cholesterol derivative shown in formula (II), formula (III), alkali are added
Ball-milling reaction 0.1～5 hours in ball grinder, after reaction completely, washing filtering, filter cake is joined in ethanol and dissolve, add
Sodium hydroxide or potassium hydroxide, control ph >=13, react 1～2 hour at 40～80 DEG C, be down to crystallizing at room temperature, filter,
To faint yellow solid, then obtain white flaky crystals 25-hydroxyl-7-DHC through ethyl alcohol recrystallization.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US10316055B2 (en) | 2015-11-30 | 2019-06-11 | Dsm Ip Assets B.V. | Crystallization of 25-hydroxy-7-dehydrocholesterol |
| WO2021120127A1 (en) | 2019-12-19 | 2021-06-24 | 湖南科瑞生物制药股份有限公司 | Method for preparing cholesterol, derivative and analogue thereof |
| CN115397832A (en) * | 2020-04-23 | 2022-11-25 | 帝斯曼知识产权资产管理有限公司 | Nanofiltration of organic solvents with 7-dehydrocholesterol or 25-hydroxy-7-dehydrocholesterol or OH protected forms thereof |
| CN111892637B (en) * | 2020-07-16 | 2022-10-14 | 山东海能生物工程有限公司 | Preparation method of 7-dehydro-25-hydroxycholesterol |
| CN113135972B (en) * | 2021-03-25 | 2022-04-19 | 江西天新药业股份有限公司 | Method for purifying 24-dehydrocholesterol |
| CN114437169B (en) * | 2022-01-25 | 2023-04-07 | 台州仙琚药业有限公司 | Synthesis method of drospirenone key intermediate bromide |
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