CN108070013A - The preparation method of 21- halogenated steroid compounds - Google Patents
The preparation method of 21- halogenated steroid compounds Download PDFInfo
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- CN108070013A CN108070013A CN201810060392.9A CN201810060392A CN108070013A CN 108070013 A CN108070013 A CN 108070013A CN 201810060392 A CN201810060392 A CN 201810060392A CN 108070013 A CN108070013 A CN 108070013A
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- PHHKQCVGNAZKGA-IXZUPGLYSA-N C[C@@H](CC(C1CC2)C3(C)CC=C1C(C)(CC1)C2=CC1=O)C3(C(CCl)=N)O Chemical compound C[C@@H](CC(C1CC2)C3(C)CC=C1C(C)(CC1)C2=CC1=O)C3(C(CCl)=N)O PHHKQCVGNAZKGA-IXZUPGLYSA-N 0.000 description 1
- OLTFGJJHHBWKTI-PUVHLWKNSA-N C[C@@H](CC(C1CC2CCC3CCC3)C3(C)CC=C1C(C)(CC1)C2=CC1=O)[C@@]3(C(OC)=C)O Chemical compound C[C@@H](CC(C1CC2CCC3CCC3)C3(C)CC=C1C(C)(CC1)C2=CC1=O)[C@@]3(C(OC)=C)O OLTFGJJHHBWKTI-PUVHLWKNSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
- C07J7/008—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21
- C07J7/0085—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21 by an halogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
- C07J71/001—Oxiranes
- C07J71/0015—Oxiranes at position 9(11)
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- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
A kind of preparation method of 21 halogenated steroid compound, comprises the following steps：Using type I compound as raw material, 21 halogenating reactions first occur with halogenating agent in the in the mixed solvent of organic solvent and water, hydrolysis occurs then at acid condition, obtains 21 halogenated steroid compounds of formula II.Above-mentioned preparation method is simple, mild condition, wide to the applicability of the 21 halogenated steroid compound of target product of formula II, and the high income of 21 halogenated steroid compounds, and purity is high, avoids the problem of conventional method synthetic route is long and yield is low.
Description
Technical field
The present invention relates to steroid preparing technical field, more particularly to a kind of system of 21- halogenated steroids compound
Preparation Method.
Background technology
Cortex hormone of aadrenaline is very important a kind of steroid hormone drug molecule, including cortisone, betamethasone and
The multi-series product such as dexamethasone all possesses 21- substituent groups in this kind of compound, most common all to have 21- hydroxyls substantially,
Such as hydrocortisone, betamethasone and fluocinolone acetonide can also continue derivative such as dexamethasone sodium phosphate, betamethasone dipropionate
And celestone-V etc., these are all to synthesize gained by 21- halogenated intermediates, also there is this body structure of some drug molecules
It is exactly 21- halo groups, such as clobetasol, momestasone furoate and Halcinonide all possess 21- chloro groups.Therefore, 21- halogen
Synthesis for steroid is extremely important.
In traditional 21- halogenated steroid compound synthesis routes, 21- is halogenated to carry out 21 hydrogen generally by halogen simple substance
Substitution reaction and obtain, be defined generally to elemental iodine or bromine list be miscellaneous, such method is there are polysubstituted phenomenon, poor, the yield of selectivity
The problems such as relatively low and production safety hidden danger.Such as by taking betamethasone as an example, traditional 21- iodo technique synthesis process are as follows, pass through
Elemental iodine substitutes, and is esterified under the conditions of potassium acetate, then hydrolyzes to obtain 21-OH, the traditional handicraft of other steroid drugs molecules
Substantially it is similar：
Also have been reported that and 21- bromo steroids are obtained by way of bromo, but it is too high using bromine simple substance activity, easily
Other double bonds or active site are acted on, side reaction is more, and yield is low.The process for synthesizing 21- chloro steroids is then more numerous
Trivial, many reports are all first by 21-OH sulfonylations, and then chloro is converted into 21- chlorine, and process steps are longer, it is necessary to from having
21- hydroxyls set out.
Also construction 21- chloro groups while side chain is introduced are had been reported that, so as to directly synthesize the method for Buprofein, this
Method is novel, and step is short, and yield is higher, but need to use the cyanide of severe toxicity, special silica reagent, and reaction process is complicated.
The content of the invention
Based on this, it is necessary to provide a kind of preparation side for the 21- halogenated steroid compounds that step is simple, yield and purity are high
Method.
A kind of preparation method of 21- halogenated steroids compound, comprises the following steps：
It is first halogenated with halogenating agent generation 21 in the in the mixed solvent of organic solvent and water using type I compound as raw material
Reaction occurs hydrolysis then at acid condition, obtains the 21- halogenated steroid compounds of formula II；The type I compound and described
The structural formula difference of the 21- halogenated steroid compounds of formula II is as follows：
Wherein, dotted line position is represented as singly-bound or double bond；
R1For carbonyl or OH；
R2For H, CH3, Cl or F；
R3For H, F, Cl, OH or without group, R4For carbonyl, OH or H；Or, R3With R4For epoxy group；
R5For H, α-CH3Or β-CH3；
R6For H, Si (CH3)3、COCH3、COCH2CH3；
R7For Si (CH3)3、COCH3、COCH2CH3、CH3Or CH2CH3；
X is halogen.
Above-mentioned preparation method is simple, mild condition, to the applicability of the target product 21- halogenated steroid compounds of formula II
Extensively, and the high income of 21- halogenated steroid compounds, purity height avoid the problem of conventional method synthetic route is long and yield is low,
So as to improve yield, energy consumption is reduced.In addition, the yield of the preparation method is relatively stablized.
In one of the embodiments, the condition of the halogenating reaction be in the presence of alkaline stabiliser in -10 DEG C~
30 DEG C of 1~4h of reaction.
In one of the embodiments, the alkaline stabiliser is in triethylamine, pyridine, sodium carbonate and sodium hydroxide
It is at least one.
In one of the embodiments, the alkaline stabiliser and the ratio of the amount of the substance of the type I compound are 0.1
~1:1.
In one of the embodiments, the halogenating agent is selected from bromo-succinimide, chlorosuccinimide, iodo
At least one of succimide, C5H6Br2N2O2, two chlordantoins, hypochlorous acid, sodium hypochlorite, hypobromous acid and sodium hypobromite.
In one of the embodiments, the halogenating agent and the ratio of the amount of the substance of the type I compound are 1~4:
1。
In one of the embodiments, the halogenating agent is chlorosuccinimide, the halogenating agent and the formula I
The ratio of the amount of the substance of compound is 1.2:1.
In one of the embodiments, the condition of the hydrolysis is to react 1~2h in 0 DEG C~60 DEG C.
In one of the embodiments, the pH value of the acid condition of the hydrolysis is 1~4.
In one of the embodiments, the step of being purified to 21- halogenated steroids compound is further included：After hydrolysis
Reaction solution adds in alkali and adjusts pH to neutrality, and concentrated solvent adds in water and is cooled to 0~10 DEG C of stirring 1~2h crystallization, filters, washing,
.
Specific embodiment
For the ease of understand the present invention, the present invention will be described more fully below, and give the present invention compared with
Good embodiment.But the present invention can realize in many different forms, however it is not limited to embodiment described herein.Phase
Instead, the purpose for providing these embodiments is the understanding more thorough and comprehensive made to the disclosure.
Unless otherwise defined, all of technologies and scientific terms used here by the article is with belonging to technical field of the invention
The normally understood meaning of technical staff is identical.Term used in the description of the invention herein is intended merely to description tool
The purpose of the embodiment of body, it is not intended that in the limitation present invention.Term as used herein "and/or" includes one or more phases
The arbitrary and all combination of the Listed Items of pass.
The preparation method of the 21- halogenated steroid compounds of one embodiment, comprises the following steps：
It is first halogenated with halogenating agent generation 21 in the in the mixed solvent of organic solvent and water using type I compound as raw material
Reaction occurs hydrolysis then at acid condition, obtains the 21- halogenated steroid compounds of formula II.
The structural formula difference of the 21- halogenated steroid compounds of type I compound and formula II is as follows：
Wherein, dotted line position is represented as singly-bound or double bond；
R1For carbonyl or OH；
R2For H, CH3, Cl or F；
R3For H, F, Cl, OH or without group, R4For carbonyl, OH or H；Or, R3With R4For epoxy group；
R5For H, α-CH3Or β-CH3；
R6For H, Si (CH3)3、COCH3、COCH2CH3；
R7For Si (CH3)3、COCH3、COCH2CH3、CH3Or CH2CH3；
X is halogen.
Above-mentioned preparation method is simple, mild condition, to the applicability of the target product 21- halogenated steroid compounds of formula II
Extensively, and the high income of 21- halogenated steroid compounds, purity height avoid the problem of conventional method synthetic route is long and yield is low,
So as to improve yield, energy consumption is reduced.In addition, the yield of the preparation method is relatively stablized.
The yield of 21- halogenated steroids compound is up to 95.6% made from the preparation method, high purity 98%.
The preparation method acts on the 20 of type I compound, 21 double bond with halogenating agent, raw after acidolysis hydrolyzes
Into 21- halogenated steroid compounds.Due to the synergistic effect of 17- oxygen atoms so that halogenating reaction has higher selectivity, so as to
So that the high selectivity of product.The reaction mechanism of the preparation method is simply as follows：
It is noted that R2For H, CH3, Cl or F；And R2For Br when, when hydrolysis occurs, can it is unstable, generation
6,7 double bonds or 6 hydroxyls, therefore impurity can be generated, yield is caused to reduce.
It is understood that type I compound buyable, can also be synthesized by reacting.In one of the embodiments, type I compound
It can be obtained by 20 carbonyls of III compound of formula by enolization, can also be built and obtained when building 17 side chains by IV compound of formula
.The structural formula of IV compound of III compound of formula and formula is as follows：
It is understood that 9,11 be singly-bound when, R4For carbonyl or OH, R3For H, F, Cl, OH or R3,R4For epoxy.Due to alkene
Hydrocarbon alcohol less stable, 9,11 be double bond when, R4For H, R3For no group.
In one of the embodiments, R1For carbonyl when, 1,2 be double bond.Due to 1,2 and 4, the double bond of 5 acts on,
Carbonyl with 3 forms relatively stable conjugated structure, therefore its α-H activity significantly reduces, and side reaction will not occur.
In one of the embodiments, Br, Cl or I.Using above-mentioned preparation method, more kinds of halogenated productions of Br, Cl or I can be prepared
Object, avoid traditional preparation method prepare 21- iodo steroids selectivity and yield it is relatively low and prepare 21- bromo steroids
The problem of side reaction of compounds of group is more, and yield is low, improve the applicability of substrate compared with.
In one of the embodiments, the condition of halogenating reaction is in -10 DEG C~30 DEG C in the presence of alkaline stabiliser
React 1~4h.Preferably, the temperature of halogenating reaction is 0~5 DEG C.
In one of the embodiments, after TLC detects halogenating reaction, further include addition reducing agent and reaction is quenched
Step.Specifically, reducing agent is sodium sulfite or sodium thiosulfate etc., with the excessive halogenating agent of quenching, prevents by-product
It generates.
Preferably, alkaline stabiliser is selected from least one of triethylamine, pyridine, sodium carbonate and sodium hydroxide.It is alkaline steady
The ratio for determining the amount of the substance of agent and type I compound is 0.1~1:1.
In one of the embodiments, halogenating agent is selected from bromo-succinimide (NBS), chlorosuccinimide
(NCS), N-iodosuccinimide (NIS), C5H6Br2N2O2, two chlordantoins, hypochlorous acid, sodium hypochlorite, hypobromous acid and sodium hypobromite
At least one of.Preferably, the ratio of the amount of halogenating agent and the substance of type I compound is 1~4:1.
Preferably, halogenating agent is chlorosuccinimide, and the ratio of the amount of the substance of halogenating agent and type I compound is
1.2:1。
In one of the embodiments, the condition of hydrolysis is to react 1~2h in 0 DEG C~60 DEG C.Preferably, hydrolysis is anti-
The temperature answered is 25~30 DEG C.
Specifically, the pH value of the acid condition of hydrolysis is 1~4.Optionally, adjust pH value used in acid for hydrochloric acid,
At least one of pyrovinic acid, p-methyl benzenesulfonic acid, sulfuric acid, perchloric acid, camphorsulfonic acid, trifluoroacetic acid and glacial acetic acid.It is preferred that
Ground, using the concentrated hydrochloric acid of 36wt%.Preferably, the pH value of the acid condition of hydrolysis is 1~2.
In one of the embodiments, organic solvent is selected from acetone, tetrahydrofuran (THF), methanol, ethyl alcohol, isopropanol, two
At least one of six ring of oxygen and N, N ,-dimethylformamide (DMF).Specifically, the volume ratio of organic solvent and water for 1~
20:1。
Preferably, the volume ratio of organic solvent and water is 5:1.
In one of the embodiments, the purification step to 21- halogenated steroid compounds is further included：By the reaction after reaction
Liquid adds in alkali and adjusts pH to neutrality, and concentrated solvent adds in water and is cooled to 0~10 DEG C of stirring 1~2h crystallization, filters, washing, i.e.,
It can.
It is specific embodiment below.
Embodiment 1
In the three-necked flask with thermometer and stirring magneton, 100g (0.364mol) chemical compounds Is a, 5mL are added in
(0.036mol) triethylamine, 500mL acetone and 100mL water, stir evenly, and system is cooled to 0~5 DEG C, by 40g (0.300mol)
NCS is slowly added into reaction bulb in batches, and process keeps 0~5 DEG C of temperature, and NCS points of 5 batches of additions add in one every 20min
Secondary, addition finishes, and continues 1~2h of insulated and stirred.TLC detection reaction raw materials completely disappear (benzene：Acetone=6:1) reaction, is stopped,
100mL 20wt% sodium sulfite solutions are added dropwise, reaction is quenched, add in the 36wt% concentrated hydrochloric acids of 30mL, pH is adjusted to about 2, system liter
Temperature to 25~30 DEG C of the reaction was continued 1~3h, TLC detection hydrolysis finishes, 20%NaOH solution is added dropwise, system is adjusted to neutrality.Decompression
Acetone is fallen in concentration, adds in 500mL water and carries out elutriation, and 0~10 DEG C of stirring 30min is filtered, and filter cake is rinsed with suitable quantity of water, and 50~60
DEG C dry compound ii a, 101g.Yield 95.6%, purity are more than 98%.Wherein yield refer to actual product quality with it is used
The percent value of the corresponding theoretical product quality of I a compounds of formula, following embodiment are similar.
Embodiment 2
In the three-necked flask with thermometer and stirring magneton, 100g (0.314mol) chemical compounds Is b, 500mL third is added in
Ketone, 100mL water and 5g (0.047mol) sodium carbonate stir evenly, and system is cooled to 5-10 DEG C, by 40g (0.300mol) NCS points
Batch is slowly added into reaction bulb, and process keeps 5~10 DEG C of temperature, and NCS points of 5 batches of additions are added in once every 20min, added
Enter to finish, continue 1~2h of insulated and stirred.TLC detection reaction raw materials completely disappear (benzene：Acetone=6:1), stop reaction, add in
Reaction stirring 30min is quenched in 20g sodium sulfite solids, and the 36wt% concentrated hydrochloric acids of 30mL are added dropwise, and system pH is adjusted to 1, is warming up to 30
~40 DEG C of the reaction was continued 1~3h, TLC detection hydrolysis finish, and 20%NaOH solution are added dropwise, system is adjusted to neutrality.It is concentrated under reduced pressure
Acetone adds in 500mL water and carries out elutriation, 0-10 DEG C of stirring 30min, filtering, and filter cake is rinsed with suitable quantity of water, and 50-60 DEG C dry
Compound ii b, 92g.Yield 93.8%, purity are more than 97%.
Embodiment 3
In the three-necked flask with thermometer and stirring magneton, 50g (0.165mol) chemical compounds Is c, 5mL are added in
(0.036mol) triethylamine, 500mL acetone and 80mL water, stir evenly, and system is cooled to 0-5 DEG C, by 30g (0.105mol) two
Bromine glycolylurea is slowly added into reaction bulb in batches, and process keeps 0~5 DEG C of temperature, 5 batches of additions of C5H6Br2N2O2 point, every 20min
It adds in once, addition finishes, and continues 0~5 DEG C of stirring 1h of heat preservation.TLC detection reaction raw materials completely disappear (benzene：Acetone=4:1),
Stop reaction, 20% sodium sulfite solutions of 100mL are added dropwise, reaction is quenched, add in the 36wt% concentrated hydrochloric acids of 30mL, system pH is adjusted to
2,25~30 DEG C are warming up to the reaction was continued 1~2h, TLC detection hydrolysis finishes, and 20wt%Na is added dropwise2CO3During system is adjusted to by solution
Property.It is directly added into 1000mL water and carries out elutriation, 0~10 DEG C of stirring 30min is filtered, and filter cake is rinsed with suitable quantity of water, and 35~45 DEG C dry
It is dry to obtain compound ii c, 96g.Yield 85%, purity are more than 95%.
Embodiment 4
Embodiment 4 is substantially the same manner as Example 1, the difference is that raw material compound and reaction temperature, with chemical compounds I
The difference of a is that 3 carbonyls replace with hydroxyl, and 6 substitute for Cl；The temperature of halogenating reaction is -10~-5 DEG C, hydrolysis
Temperature is 55~60 DEG C.Yield is 82%, purity 93%.
Embodiment 5
Embodiment 5 is substantially the same manner as Example 1, the difference is that raw material compound and reaction temperature, with chemical compounds I
The difference of a is that 17 hydroxyls replace with OSi (CH3)3, 20 methyl ether groups replace with OSi (CH3)3；The temperature of halogenating reaction
It spends for 25~30 DEG C, the temperature of hydrolysis is 0~5 DEG C.Yield is 94%, purity 97%.
Embodiment 6
Embodiment 6 is substantially the same manner as Example 3, the difference is that raw material compound, it is different from chemical compounds I c's
OCOCH is replaced in 17 hydroxyls3, 11 carbonyls replace with hydroxyl.Yield is 89%, purity 96%.
Embodiment 7
Embodiment 7 is substantially the same manner as Example 1, the difference is that NCS to be replaced with etc. to the NIS of the amount of quality.Drying
Temperature is no more than 30 DEG C, yield 91%, purity 92%.
Embodiment 8
Embodiment 8 is substantially the same manner as Example 1, the difference is that the addition of triethylamine and NCS, the addition of triethylamine
Amount and the amount equivalent of the substance of chemical compounds I a, the addition of NCS are 4 times of the amount of the substance of chemical compounds I a.Yield 96%, purity
98%.
Comparative example 1
Comparative example 1 is substantially the same manner as Example 1, the difference is that raw material compound, it is different from chemical compounds I a's
Substitute in 6 for Br.Yield is 56%, purity 88%.
Each technical characteristic of embodiment described above can be combined arbitrarily, to make description succinct, not to above-mentioned reality
It applies all possible combination of each technical characteristic in example to be all described, as long as however, the combination of these technical characteristics is not deposited
In contradiction, the scope that this specification is recorded all is considered to be.
Embodiment described above only expresses the several embodiments of the present invention, and description is more specific and detailed, but simultaneously
It cannot therefore be construed as limiting the scope of the patent.It should be pointed out that come for those of ordinary skill in the art
It says, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to the protection of the present invention
Scope.Therefore, the protection domain of patent of the present invention should be determined by the appended claims.
Claims (10)
1. a kind of preparation method of 21- halogenated steroids compound, which is characterized in that comprise the following steps：
Using type I compound as raw material, 21 halogenating reactions first occur with halogenating agent in the in the mixed solvent of organic solvent and water,
Hydrolysis occurs then at acid condition, obtains the 21- halogenated steroid compounds of formula II；The type I compound and the formula II
21- halogenated steroid compounds structural formula difference it is as follows：
Wherein, dotted line position is represented as singly-bound or double bond；
R1For carbonyl or OH；
R2For H, CH3, Cl or F；
R3For H, F, Cl, OH or without group, R4For carbonyl, OH or H；Or, R3With R4For epoxy group；
R5For H, α-CH3Or β-CH3；
R6For H, Si (CH3)3、COCH3、COCH2CH3；
R7For Si (CH3)3、COCH3、COCH2CH3、CH3Or CH2CH3；
X is halogen.
2. the preparation method of 21- halogenated steroids compound as described in claim 1, which is characterized in that the halogenating reaction
Condition is to react 1~4h in -10 DEG C~30 DEG C in the presence of alkaline stabiliser.
3. the preparation method of 21- halogenated steroids compound as claimed in claim 2, which is characterized in that the alkaline stabiliser
Selected from least one of triethylamine, pyridine, sodium carbonate and sodium hydroxide.
4. the preparation method of 21- halogenated steroids compound as claimed in claim 3, which is characterized in that the alkaline stabiliser
Ratio with the amount of the substance of the type I compound is 0.1~1:1.
5. such as the preparation method of Claims 1 to 4 any one of them 21- halogenated steroid compounds, which is characterized in that the halogen
Bromo-succinimide, chlorosuccinimide, N-iodosuccinimide, C5H6Br2N2O2, two chlordantoins, secondary chlorine are selected from for reagent
At least one of acid, sodium hypochlorite, hypobromous acid and sodium hypobromite.
6. the preparation method of 21- halogenated steroids compound as claimed in claim 5, which is characterized in that the halogenating agent with
The ratio of the amount of the substance of the type I compound is 1~4:1.
7. the preparation method of 21- halogenated steroids compound as claimed in claim 6, which is characterized in that the halogenating agent is
The ratio of chlorosuccinimide, the halogenating agent and the amount of the substance of the type I compound is 1.2:1.
8. the preparation method of 21- halogenated steroids compound as described in claim 1, which is characterized in that the hydrolysis
Condition is to react 1~2h in 0 DEG C~60 DEG C.
9. the preparation method of the 21- halogenated steroid compounds as described in claim 1 or 8, which is characterized in that the hydrolysis
Acid condition pH value be 1~4.
10. such as the preparation method of Claims 1 to 4 any one of them 21- halogenated steroid compounds, which is characterized in that also wrap
Include the step of being purified to 21- halogenated steroids compound：Reaction solution after hydrolysis is added in into alkali and adjusts pH to neutrality, concentration is molten
Agent adds in water and is cooled to 0~10 DEG C of stirring 1~2h crystallization, filters, washing, you can.
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| CN109369762A (en) * | 2018-10-31 | 2019-02-22 | 湖南玉新药业有限公司 | The preparation method of 17- formic acid steroid |
| CN112341510A (en) * | 2020-11-12 | 2021-02-09 | 湖南新合新生物医药有限公司 | Preparation method of betamethasone |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109369762A (en) * | 2018-10-31 | 2019-02-22 | 湖南玉新药业有限公司 | The preparation method of 17- formic acid steroid |
| CN109369762B (en) * | 2018-10-31 | 2021-06-18 | 湖南玉新药业有限公司 | Process for the preparation of 17-carboxylic acid steroids |
| CN112341510A (en) * | 2020-11-12 | 2021-02-09 | 湖南新合新生物医药有限公司 | Preparation method of betamethasone |
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