CN108659084A - A kind of preparation method of 17 β-carboxylic acids chloromethane esters steroidal compounds - Google Patents
A kind of preparation method of 17 β-carboxylic acids chloromethane esters steroidal compounds Download PDFInfo
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- CN108659084A CN108659084A CN201710210437.1A CN201710210437A CN108659084A CN 108659084 A CN108659084 A CN 108659084A CN 201710210437 A CN201710210437 A CN 201710210437A CN 108659084 A CN108659084 A CN 108659084A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
- C07J5/0053—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa not substituted in position 16
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J13/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17
- C07J13/005—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17 with double bond in position 16 (17)
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
- C07J5/0061—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16
- C07J5/0069—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group
- C07J5/0076—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group by an alkyl group
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- 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
- C07J71/0026—Oxygen-containing hetero ring cyclic ketals
- C07J71/0031—Oxygen-containing hetero ring cyclic ketals at positions 16, 17
Abstract
The invention discloses a kind of preparation methods of 17 β carboxylic acids chloromethane esters steroidal compounds, under alkaline condition, using dichloromethane as chloromethylation reagents, obtain 17 β carboxylic acid chloromethane esters steroidal compounds.This process conditions is mild, and agents useful for same is easy to get, and simplifies operating procedure, cost reduction, and yield improves, and more environmentally-friendly, is suitble to industrialized production.
Description
Technical field
The present invention relates to a kind of preparation methods of 17 β-carboxylic acids chloromethane esters steroidal compounds, belong to steroidal synthetic technology neck
Domain.
Background technology
17 β-carboxylic acid chloromethane esters steroidal compounds are a kind of important steroid drugs or pharmaceutical intermediate structure, document report
Chloromethylation reagents used in the preparation of the 17 β-carboxylic acid chloromethane esters steroidal compounds in road include mainly chloroiodomethane, chlorine bromine first
Alkane, chlorosulfonic acid chloromethyl ester etc., above-mentioned chloromethylation reagents all have irritation and hostile environment, such as chlorobromomethane has stimulation
Property, it is easy to be damaged by human body sucking, it is also harmful to environment, water body and soil can be polluted, are easy in organism
Middle accumulation.
Patent US4996335, US4710495, WO200403982717, WO03072592, CN1224429 and Chen Aijun's
《The improvement in synthesis of Loteprednol》In, using the chloroiodomethane of 2.7-6.5 times of equivalent as chloromethylation reagents, yield
53%-86.7%, chloroiodomethane is expensive, and dosage is larger, of high cost；Patent CN201180008214 and
CN103391945 is using 5 times of equivalent chlorobromomethanes as chloromethylation reagents, and yield 24%, this method chlorobromomethane dosage is larger, and
Yield is too low；Patent CN103183714 and document " Steorid Biochem MOL BIOL, 1991,38 (2)：149-154”
Using 1.6 times of equivalent chlorosulfonic acid chloromethyl esters as chloromethylation reagents, yield 106%, the reagent have intense irritation, toxicity compared with
Greatly, it is not suitable for mass producing；Patent CN103249716 uses (chloromethyl) (phenyl) (2,3,4,5- tetramethylphenyls) sulfonium
Fluoroform sulphonate or chloromethyl) (phenyl) (2,3,4,5- tetramethylphenyl) sulfonium tetrafluoroborate as chloromethylation reagents,
Yield 88%-135%, this method agents useful for same are not easy to obtain, make troubles to actual production；Patent CN1224429 is with 3.75
The chloro sulfuric acid chloromethyl ester of times equivalent is chloromethylation reagents；Patent US4710495 is with 1.1 times of equivalent chloromethyl chloro sulfate
As chloromethylation reagents.
Above method production cost is high, and reaction system is complicated, and generation impurity is more, and post-processing is cumbersome, and therefore, exploitation is a kind of
New 17 β-carboxylic acid chloromethane esters steroidal compounds preparation processes are of great significance.
Invention content
The object of the present invention is to provide a kind of 17 β-carboxylic acid chloromethane esters steroidal compounds at low cost, production efficiency is high
Preparation method.
A kind of preparation method of 17 β-carboxylic acids chloromethane esters steroidal compounds, it is characterised in that steps are as follows：
Under alkaline condition, compound A is reacted with dichloromethane, obtains 17 β-carboxylic acid chloromethane esters steroidal compounds B,
For singly-bound or double bond
R1、R2、R3、R4、R5Independently of one another selection and wherein：
R1=α-OH, β-OH ,-H or=O
R2=α-Cl, α-Br, α-F or α-H
Or R1And R29 β, 11 beta epoxides can be formed together
R3=F, Cl, CH3、H
R4=-H, α-OH, α-OCOOR6, R6For the alkyl within six carbon
R5=-H, α-OH, α-CH3、β-CH3
Or R4And R5The part of part or Formula II with Formulas I can be formed together：
For wherein X and Y independently selected from hydrogen or alkyl, condition is when one of X or Y are hydrogen, the other is alkyl；
Work as R2When=α-Br or α-F, R1=β-OH
Work as R1For=O when, R2=α-H.
A kind of preparation method of the 17 β-carboxylic acids chloromethane esters steroidal compounds, it is characterised in that：
For singly-bound
R1=β-OH or=O
R2=α-H
R3=H
R4=α-OCOOR6, R6For the alkyl within three carbon
R5=-H.
A kind of preparation method of the 17 β-carboxylic acids chloromethane esters steroidal compounds, it is characterised in that：Alkali type used
One kind in inorganic base, alkyl amine, secondary amine, aromatic amine.
A kind of preparation method of the 17 β-carboxylic acids chloromethane esters steroidal compounds, it is characterised in that：The inorganic base
Selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, saleratus, sulfurous acid
One kind in sodium；The one kind of the alkyl amine in triethylamine, Trimethylamine；The secondary amine is selected from diethylamide, diformazan
One kind in base amine；The one kind of the aromatic amine in 4-dimethylaminopyridine, pyridine, quinoline.
A kind of preparation method of the 17 β-carboxylic acids chloromethane esters steroidal compounds, it is characterised in that：In reaction system
Cosolvent is added, the cosolvent is selected from dimethylformamide, dimethylacetylamide, hydroxy propyl methacrylate, methanol, six
It is one or more in methyl phosphamide.
A kind of preparation method of the 17 β-carboxylic acids chloromethane esters steroidal compounds, it is characterised in that：In reaction system
Add surfactant, the one kind of the surfactant in 4-butyl ammonium hydrogen sulfate, benzyltriethylammoinium chloride.
A kind of preparation method of the 17 β-carboxylic acids chloromethane esters steroidal compounds, it is characterised in that：By quality ratio
It calculates, the rate of charge of the surfactant and compound A are 0.05-0.1：1.
A kind of preparation method of the 17 β-carboxylic acids chloromethane esters steroidal compounds, it is characterised in that：In reaction system
Add auxiliary agent, the one kind of the auxiliary agent in sodium iodide, sodium bromide.
A kind of preparation method of the 17 β-carboxylic acids chloromethane esters steroidal compounds, it is characterised in that：By quality ratio
It calculates, the rate of charge of the auxiliary agent and compound A are 0.05-0.1：1.
A kind of preparation method of the 17 β-carboxylic acids chloromethane esters steroidal compounds, it is characterised in that：Reaction temperature is selected
From 20-50 DEG C.
Basic catalyst is added in chloromethylation in the present invention, is produced using dichloromethane as chloromethylation reagents
17 β-carboxylic acid chloromethane esters steroidal compounds, dichloromethane is cheap, and recyclable, greatly reduces cost, reduces
The generation of impurity, simplifies later stage purification procedures, and more environmentally-friendly, is suitble to large-scale production.In addition, this technique is logical
It crosses and auxiliary agent sodium iodide or sodium bromide is added in the reaction system, reaction temperature reduces, and yield and purity significantly improve.
Specific implementation mode
Below will by embodiment, the invention will be further described, these description be not to the content of present invention make into
The restriction of one step.Related technical personnel should be understood that equivalent replacement made by the technical characteristic to the present invention, or be correspondingly improved,
It still falls within protection scope of the present invention.
Embodiment 1 is with compound 1 for starting material prepare compound 2
Embodiment 1-1
6g saleratus and 150ml dimethylformamides are added into 500ml reaction bulbs, stirs evenly at room temperature, to anti-
It answers and 30.0g compounds 1 and dichloromethane 60ml is added in bottle, stirring is warming up to 45 DEG C and reacts 2 hours after 1 hour, TLC monitorings are anti-
It answers process to reaction to terminate, reaction solution is diluted in 1500ml water, stirring is filtered after 1 hour, dry, and absolute ethyl alcohol weight is added
Crystallization filters, and 22.4g compounds 2, mass yield 74.6%, purity 95.3% are obtained after dry.
Embodiment 1-2
5g potassium carbonate and 150ml methanol are added into 500ml reaction bulbs, stirs evenly, is added into reaction bulb at room temperature
30.0g compounds 1 and dichloromethane 60ml, stirring are warming up to 45 DEG C and react 2 hours after 1 hour, TLC monitors reaction process to anti-
It should terminate, reaction solution is diluted in 1500ml water, stirring is filtered after 1 hour, dry, and absolute ethyl alcohol recrystallization is added, filters,
21.9g compounds 2, mass yield 73.0%, purity 97.0% are obtained after drying.
Embodiment 1-3
5g lithium hydroxides and 150ml dimethylacetylamides are added into 500ml reaction bulbs, stirs evenly at room temperature, to anti-
It answers and 30.0g compounds 1 and dichloromethane 60ml is added in bottle, be stirred to react 2 hours, TLC monitoring reaction process to reactions terminate,
Reaction solution is diluted in 1500ml water, stirring is filtered after 1 hour, dry, and absolute ethyl alcohol recrystallization is added, filters, after dry
Obtain 22.0g compounds 2, mass yield 73.5%, purity 96.3%.
Embodiment 1-4
Embodiment 1-4-a
4g cesium carbonates and 210ml dichloromethane are added into 500ml reaction bulbs, stirs evenly at room temperature, into reaction bulb
30.0g compounds 1 and benzyltriethylammoinium chloride 1.5g and sodium bromide 1.5g is added, is stirred to react 2 hours, TLC monitoring reactions
Process to reaction terminates, and dichloromethane layer is washed once with 300ml, and anhydrous sodium sulfate is added and dries 1 hour, filters, concentration steaming
Dry dichloromethane is added absolute ethyl alcohol recrystallization, filters, and 24g compounds 2, mass yield 80.0%, purity are obtained after dry
98.8%.
Embodiment 1-4-b
4g cesium carbonates and 210ml dichloromethane are added into 500ml reaction bulbs, stirs evenly at room temperature, into reaction bulb
30.0g compounds 1 and benzyltriethylammoinium chloride 1.5g is added, stirring is warming up to 45 DEG C and reacts 3 hours after 1 hour, TLC monitorings
Reaction process to reaction terminates, and dichloromethane layer is washed once with 300ml, and anhydrous sodium sulfate is added and dries 1 hour, filters, dense
Contracting is evaporated dichloromethane, and absolute ethyl alcohol recrystallization is added, filters, it is dry after 21.0g compounds 2, mass yield 70.0%,
Purity 95.8%.
Embodiment 1-5
6ml triethylamines and 150ml hexamethyl phosphoramides are added into 500ml reaction bulbs, stirs evenly at room temperature, to reaction
30.0g compounds 1 and 60ml dichloromethane are added in bottle, stirring is warming up to 45 DEG C and reacts 2 hours after 1 hour, TLC monitoring reactions
Process to reaction terminates, and reaction solution is diluted in 1500ml water, and stirring is filtered after 1 hour, dry, and absolute ethyl alcohol is added and ties again
Crystalline substance filters, and 22.2g compounds 2, mass yield 74.0%, purity 96.2% are obtained after dry.
Embodiment 1-6
6g sodium sulfites and 210ml dichloromethane are added into 500ml reaction bulbs, stirs evenly at room temperature, to reaction bulb
Middle addition 30.0g compounds 1 and 4-butyl ammonium hydrogen sulfate 1.8g, stirring are warming up to 45 DEG C and react 2.5 hours after 1 hour, TLC prisons
Reaction process to reaction to be surveyed to terminate, dichloromethane layer is washed once with 300ml, and anhydrous sodium sulfate is added and dries 1 hour, filters,
It concentrates and is evaporated dichloromethane, absolute ethyl alcohol recrystallization is added, filters, obtain 21.1g compounds 2 after dry, mass yield is
70.3%, purity 95.8%.
Embodiment 1-7
Embodiment 1-7-a
3g sodium hydroxides and 210ml dichloromethane are added into 500ml reaction bulbs, stirs evenly at room temperature, to reaction bulb
Middle addition 30.0g compounds 1 and sodium iodide 2.5g, are stirred to react 1.5 hours, and TLC monitoring reaction process to reactions terminate, dichloro
Methane layer is washed once with 300ml, and anhydrous sodium sulfate is added and dries 1 hour, filters, and concentration is evaporated dichloromethane, and addition is anhydrous
Ethyl alcohol recrystallization filters, and 23.8g compounds 2, mass yield 79.5%, purity 98.0% are obtained after dry.
Embodiment 1-7-b
3g sodium hydroxides and 210ml dichloromethane are added into 500ml reaction bulbs, stirs evenly at room temperature, to reaction bulb
Middle addition 30.0g compounds 1, stirring are warming up to 45 DEG C and react 3 hours after 1 hour, TLC monitoring reaction process to reactions terminate,
Dichloromethane layer is washed once with 300ml, and anhydrous sodium sulfate is added and dries 1 hour, filters, and concentration is evaporated dichloromethane, addition
Absolute ethyl alcohol recrystallizes, and filters, and 21.4g compounds 2, mass yield 71.5%, purity 95.0% are obtained after dry.
Embodiment 1-8
5ml pyridines and 210ml dichloromethane are added into 500ml reaction bulbs, stirs evenly at room temperature, adds into reaction bulb
Enter 30.0g compounds 1, stirring is warming up to 45 DEG C and reacts 4 hours after 1 hour, TLC monitoring reaction process to reactions terminate, dichloro
Methane layer is washed once with 300ml, and anhydrous sodium sulfate is added and dries 1 hour, filters, and concentration is evaporated dichloromethane, and addition is anhydrous
Ethyl alcohol recrystallization filters, and 19.5g compounds 2, mass yield 65.0%, purity 95.3% are obtained after dry.
Embodiment 2 is with compound 3 for starting material prepare compound 4
Embodiment 2-1
6g sodium hydroxides and 150ml dimethylacetylamides are added into 500ml reaction bulbs, stirs evenly at room temperature, to anti-
It answers and 30.0g compounds 3 is added in bottle, being warming up to 48 DEG C after dichloromethane 60ml stirrings being added 1 hour reacts 2 hours, TLC monitorings
Reaction process to reaction terminates, and reaction solution is diluted in 1500ml water, and stirring is filtered after 1 hour, dry, and absolute ethyl alcohol is added
Recrystallization filters, and 22.9g compounds 4, mass yield 76.2%, purity 95.0% are obtained after dry.
Embodiment 2-2
6g sodium hydroxides and 210ml dichloromethane are added into 500ml reaction bulbs, stirs evenly at room temperature, to reaction bulb
Middle addition 30.0g compounds 3 and sodium iodide 2.0g are stirred to react 1.5 hours, and TLC monitoring reaction process to reactions terminate, dichloro
Methane layer is washed once with 300ml, and anhydrous sodium sulfate is added and dries 1 hour, filters, and concentration is evaporated dichloromethane, and addition is anhydrous
Ethyl alcohol recrystallization filters, and 22.8g compounds 4, mass yield 79.2%, purity 98.5% are obtained after dry.
Embodiment 3 is with compound 5 for starting material prepare compound 6
Embodiment 3-1
5g potassium carbonate and 210ml dichloromethane are added into 500ml reaction bulbs, stirs evenly at room temperature, into reaction bulb
30.0g compounds 5 are added, sodium iodide 1.5g is added under stirring condition, is stirred to react 1.5 hours, TLC monitors reaction process to anti-
It should terminate, dichloromethane layer is washed once with 300ml, and anhydrous sodium sulfate is added and dries 1 hour, filters, concentration is evaporated dichloromethane
Alkane is added absolute ethyl alcohol recrystallization, filters, and 24.5g compounds 6, mass yield 80.6%, purity 98.8% are obtained after dry.
Embodiment 3-2
5g potassium carbonate and 210ml dichloromethane are added into 500ml reaction bulbs, stirs evenly at room temperature, into reaction bulb
30.0g compounds 5 are added, 4-butyl ammonium hydrogen sulfate 1.5g is added under stirring condition, stirring is warming up to 40 DEG C of reactions 2 after 1 hour
Hour, TLC monitoring reaction process to reactions terminate, and dichloromethane layer washes primary, addition anhydrous sodium sulfate drying 1 with 300ml
Hour, it filters, concentrates and be evaporated dichloromethane, absolute ethyl alcohol recrystallization is added, filters, 22.6g compounds 6, quality are obtained after dry
Yield is 75.3%, purity 96.2%.
Embodiment 4 is with compound 7 for starting material prepare compound 8
Embodiment 4-1
5g 4-dimethylaminopyridine and 150ml hexamethyl phosphoramides are added into 500ml reaction bulbs, stirring is equal at room temperature
It is even, 30.0g compounds 7 are added into reaction bulb, dichloromethane 60ml are added, stirring is warming up to 40 DEG C of reactions 2 after 1 hour small
When, TLC monitoring reaction process to reactions terminate, and reaction solution is diluted in 1500ml water, and stirring is filtered after 1 hour, dry, is added
Enter absolute ethyl alcohol recrystallization, filter, 21.4g compounds 8, mass yield 71.3%, purity 96.1% are obtained after dry.
Embodiment 4-2
5g 4-dimethylaminopyridine and 210ml dichloromethane are added into 500ml reaction bulbs, stirs evenly at room temperature, to
30.0g compounds 7 and sodium iodide 2.5g are added in reaction bulb, is stirred to react 1.5 hours, TLC monitors reaction process to reacting knot
Beam, dichloromethane layer are washed once with 300ml, and anhydrous sodium sulfate is added and dries 1 hour, filters, concentration is evaporated dichloromethane, adds
Enter absolute ethyl alcohol recrystallization, filter, 22.9g compounds 8, mass yield 76.3%, purity 98.1% are obtained after dry.
Embodiment 5 is with compound 9 for starting material prepare compound 10
Embodiment 5-1
4ml triethylamines and 210ml dichloromethane are added into 500ml reaction bulbs, stirs evenly at room temperature, into reaction bulb
30.0g compounds 9 are added, sodium bromide 2.5g is added, is stirred to react 1.5 hours, TLC monitoring reaction process to reactions terminate, and two
Chloromethanes layer is washed once with 300ml, and anhydrous sodium sulfate is added and dries 1 hour, filters, and concentration is evaporated dichloromethane, addition nothing
Water-ethanol recrystallizes, and filters, and 23.8g compounds 10, mass yield 79.3%, purity 97.8% are obtained after dry.
Embodiment 5-2
4ml triethylamines and 210ml dichloromethane are added into 500ml reaction bulbs, stirs evenly at room temperature, into reaction bulb
30.0g compounds 9 are added, benzyltriethylammoinium chloride 2.5g is added, stirring is warming up to 40 DEG C and reacts 2 hours after 1 hour, TLC
Monitoring reaction process to reaction terminates, and dichloromethane layer is washed once with 300ml, and anhydrous sodium sulfate is added and dries 1 hour, takes out
Filter concentrates and is evaporated dichloromethane, and absolute ethyl alcohol recrystallization is added, filters, and obtains 22.6g compounds 10 after dry, mass yield is
75.3%, purity 95.8%.
Embodiment 6 is with compound 11 for starting material prepare compound 12
Embodiment 6-1
6ml quinoline and 150ml hexamethyl phosphoramides are added into 500ml reaction bulbs, stirs evenly at room temperature, to reaction bulb
Middle addition 30.0g compounds 11 and dichloromethane 60ml, stirring are warming up to 40 DEG C and react 2 hours after 1 hour, TLC monitoring reactions
Process to reaction terminates, and reaction solution is diluted in 1500ml water, and stirring is filtered after 1 hour, dry, and absolute ethyl alcohol is added and ties again
Crystalline substance filters, and 22.0g compounds 12, mass yield 73.3%, purity 94.6% are obtained after dry.
Embodiment 6-2
6ml quinoline and 210ml dichloromethane are added into 500ml reaction bulbs, stirs evenly at room temperature, adds into reaction bulb
Enter 30.0g compounds 11 and 2.5g sodium iodides are stirred to react 1.5 hours, TLC monitoring reaction process to reactions terminate, by reaction solution
It is diluted in 1500ml water, stirring is filtered after 1 hour, drying, and absolute ethyl alcohol recrystallization is added, filters, and 23.2gization is obtained after dry
Close object 12, mass yield 77.3%, purity 97.6%.
Embodiment 7 is with compound 13 for starting material prepare compound 14
Embodiment 7-1
6ml pyridines and 210ml dichloromethane are added into 500ml reaction bulbs, stirs evenly at room temperature, adds into reaction bulb
Enter 30.0g compounds 13 and sodium iodide 1.8g, be stirred to react 1.5 hours, TLC monitoring reaction process to reactions terminate, dichloromethane
Alkane layer is washed once with 300ml, and anhydrous sodium sulfate is added and dries 1 hour, filters, concentration is evaporated dichloromethane, and anhydrous second is added
Alcohol recrystallizes, and filters, and 24.0g compounds 14, mass yield 79.8%, purity 97.8% are obtained after dry.
Embodiment 7-2
6ml pyridines and 210ml dichloromethane are added into 500ml reaction bulbs, stirs evenly at room temperature, adds into reaction bulb
Enter 30.0g compounds 13 and 4-butyl ammonium hydrogen sulfate 1.8g, stirring is warming up to 40 DEG C and reacts 2.5 hours after 1 hour, TLC monitorings
Reaction process to reaction terminates, and dichloromethane layer is washed once with 300ml, and anhydrous sodium sulfate is added and dries 1 hour, filters, dense
It contracts and is evaporated dichloromethane, absolute ethyl alcohol recrystallization is added, filters, obtain 22.4g compounds 14 after dry, mass yield is
74.8%, purity 94.8%.
Embodiment 8 is with compound 15 for starting material prepare compound 16
Embodiment 8-1
5g cesium carbonates and 150ml methanol are added into 500ml reaction bulbs, stirs evenly, is added into reaction bulb at room temperature
30.0g compounds 15 and dichloromethane 60ml, stirring are warming up to 40 DEG C and react 2.5 hours after 1 hour, TLC monitors reaction process
Terminating to reaction, reaction solution is diluted in 1500ml water, stirring is filtered after 1 hour, dry, and absolute ethyl alcohol recrystallization is added,
It filters, 22.3g compounds 16, mass yield 74.3%, purity 94.3% is obtained after dry.
Embodiment 8-2
5g cesium carbonates and 210ml dichloromethane are added into 500ml reaction bulbs, stirs evenly at room temperature, into reaction bulb
30.0g compounds 15 and sodium bromide 2.0g is added, is stirred to react 2 hours, TLC monitoring reaction process to reactions terminate, dichloromethane
Alkane layer is washed once with 300ml, and anhydrous sodium sulfate is added and dries 1 hour, filters, concentration is evaporated dichloromethane, and anhydrous second is added
Alcohol recrystallizes, and filters, and 23.5g compounds 16, mass yield 78.3%, purity 98.3% are obtained after dry.
Embodiment 9 is with compound 17 for starting material prepare compound 18
Embodiment 9-1
6g sodium sulfites and 210ml dichloromethane are added into 500ml reaction bulbs, stirs evenly at room temperature, to reaction bulb
Middle addition 30.0g compounds 17 and sodium bromide 2.3g, are stirred to react 2 hours, and TLC monitoring reaction process to reactions terminate, dichloro
Methane layer is washed once with 300ml, and anhydrous sodium sulfate is added and dries 1 hour, filters, and concentration is evaporated dichloromethane, and addition is anhydrous
Ethyl alcohol recrystallization filters, and 22.6g compounds 18, mass yield 75.3%, purity 96.6% are obtained after dry.
Embodiment 9-2
6g sodium sulfites and 210ml dichloromethane are added into 500ml reaction bulbs, stirs evenly at room temperature, to reaction bulb
Middle addition 30.0g compounds 17, are stirred to react 4 hours, and TLC monitoring reaction process to reactions terminate, dichloromethane layer 300ml
Washing is primary, and anhydrous sodium sulfate is added and dries 1 hour, filters, and concentration is evaporated dichloromethane, and absolute ethyl alcohol recrystallization is added, takes out
Filter obtains 18g compounds 18, mass yield 60%, purity 86.6% after dry.
Embodiment 10 is with compound 19 for starting material prepare compound 20
Embodiment 10-1
6ml Trimethylamines and 150ml dimethylformamides are added into 500ml reaction bulbs, stirs evenly at room temperature, to anti-
It answers and 30.0g compounds 19 and dichloromethane 60ml is added in bottle, stirring is warming up to 40 DEG C and reacts 3 hours after 1 hour, TLC monitorings
Reaction process to reaction terminates, and reaction solution is diluted in 1500ml water, and stirring is filtered after 1 hour, dry, and absolute ethyl alcohol is added
Recrystallization filters, and 22.0g compounds 20, mass yield 73.4%, purity 95.3% are obtained after dry.
Embodiment 10-2
6ml Trimethylamines and 150ml dimethylformamides are added into 500ml reaction bulbs, stirs evenly at room temperature, to anti-
It answers and 30.0g compounds 19, dichloromethane 60ml and sodium iodide 2.5g is added in bottle, be stirred to react at room temperature 1.5 hours, TLC prisons
It surveys reaction process to reaction to terminate, reaction solution is diluted in 1500ml water, stirring is filtered after 1 hour, dry, and anhydrous second is added
Alcohol recrystallizes, and filters, and 24.1g compounds 20, mass yield 80.4%, purity 98.3% are obtained after dry.
Claims (10)
1. a kind of preparation method of 17 β-carboxylic acids chloromethane esters steroidal compounds, it is characterised in that steps are as follows：
Under alkaline condition, compound A is reacted with dichloromethane, obtains 17 β-carboxylic acid chloromethane esters steroidal compounds B,
For singly-bound or double bond
R1、R2、R3、R4、R5Independently of one another selection and wherein：
R1=α-OH, β-OH ,-H or=O
R2=α-Cl, α-Br, α-F or α-H
Or R1And R29 β, 11 beta epoxides can be formed together
R3=F, Cl, CH3、H
R4=-H, α-OH, α-OCOOR6, R6For the alkyl within six carbon
R5=-H, α-OH, α-CH3、β-CH3
Or R4And R5The part of part or Formula II with Formulas I can be formed together：
For wherein X and Y independently selected from hydrogen or alkyl, condition is when one of X or Y are hydrogen, the other is alkyl；
Work as R2When=α-Br or α-F, R1=β-OH
Work as R1For=O when, R2=H.
2. a kind of preparation method of 17 β-carboxylic acids chloromethane esters steroidal compounds as described in claim 1, it is characterised in that：
For singly-bound
R1=β-OH or=O
R2=α-H
R3=H
R4=α-OCOOR6, R6For the alkyl within three carbon
R5=-H.
3. a kind of preparation method of 17 β-carboxylic acids chloromethane esters steroidal compounds as described in claim 1-2 is any, feature
It is：
The one kind of alkali type used in inorganic base, alkyl amine, secondary amine, aromatic amine.
4. a kind of preparation method of 17 β-carboxylic acids chloromethane esters steroidal compounds as claimed in claim 3, it is characterised in that：
The inorganic base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, carbon
One kind in potassium hydrogen phthalate, sodium sulfite；The one kind of the alkyl amine in triethylamine, Trimethylamine；The secondary amine is selected from
One kind in diethylamide, dimethyl amine；The one kind of the aromatic amine in 4-dimethylaminopyridine, pyridine, quinoline.
5. a kind of preparation method of 17 β-carboxylic acids chloromethane esters steroidal compounds as described in claim 1-2 is any, feature
It is：
Cosolvent is added in reaction system, the cosolvent is selected from dimethylformamide, dimethylacetylamide, methacrylic acid
It is one or more in hydroxypropyl acrylate, methanol, hexamethyl phosphoramide.
6. a kind of preparation method of 17 β-carboxylic acids chloromethane esters steroidal compounds as described in claim 1-2 is any, feature
It is：
Surfactant is added in reaction system, the surfactant is selected from 4-butyl ammonium hydrogen sulfate, benzyl triethyl ammonium chlorine
Change one kind in ammonium.
7. a kind of preparation method of 17 β-carboxylic acids chloromethane esters steroidal compounds as claimed in claim 6, it is characterised in that：
It calculates by quality ratio, the rate of charge of the surfactant and compound A are 0.05-0.1：1.
8. a kind of preparation method of 17 β-carboxylic acids chloromethane esters steroidal compounds as described in claim 1-2 is any, feature
It is：
Auxiliary agent, the one kind of the auxiliary agent in sodium iodide, sodium bromide are added in reaction system.
9. a kind of preparation method of 17 β-carboxylic acids chloromethane esters steroidal compounds as claimed in claim 8, it is characterised in that：
It calculates by quality ratio, the rate of charge of the auxiliary agent and compound A are 0.05-0.1：1.
10. a kind of preparation method of 17 β-carboxylic acids chloromethane esters steroidal compounds as described in claim 1-2 is any, feature
It is：
Reaction temperature is selected from 20-50 DEG C.
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