CN104558091B - A kind of synthetic method of Abiraterone acetate - Google Patents
A kind of synthetic method of Abiraterone acetate Download PDFInfo
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- CN104558091B CN104558091B CN201310484373.6A CN201310484373A CN104558091B CN 104558091 B CN104558091 B CN 104558091B CN 201310484373 A CN201310484373 A CN 201310484373A CN 104558091 B CN104558091 B CN 104558091B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
Abstract
The synthetic method of Abiraterone acetate is prepared by steps such as esterification, form, dehydration, acylation, reduction, acetylations to enlighten thing with compound 1 the present invention relates to one kind.
Description
Technical field
The present invention relates to chemosynthesis technical field, and in particular to a kind of synthesis side of steroid drugs Abiraterone acetate
Method.
Background technology
Abiraterone acetate (abiraterone acetate, 1), chemistry entitled 32- acetoxyl group -17- (3- pyridines
Base)-androstane -5,16- diene is that a kind of orally active CYP17 enzymes developed by Centocor Ortho companies of the U.S. can not
Retroactive inhibition agent, ratifies to list in April, 2011 through U.S. FDA, clinical to be combined treatment castration resistance with metacortandracin (prednisone)
Property prostate cancer (castration resistant prostatecancer, CRPC).This product is key enzyme 17 in testosterone synthesis
The selective oral inhibitor of ±-hydroxylase-C17,20- lyases (human-cytochrome P45017 enzymes), can reduce tumour mark
The level of will thing PSA (PSA), available for those using drug therapy or underwent operative excision and tumour after
The continuous patients with prostate cancer increased.
The synthetic route of Abiraterone acetate mainly has two：
Route 1 obtains steroids enol trifluoro using dehydrobenzene as raw material by acylation, with trifluoromethanesulfonic acid anhydride reactant
Metilsulfate, is then obtained, total recovery is 48.7% with the reaction of diethyl (3- pyridine radicals) borine.
Have the disadvantages that：Diethyl (3- pyridine radicals) borine and trifluoromethanesulfanhydride anhydride price are all very expensive, are produced into
This is higher；In the synthetic route during prepare compound 3, this step reaction of document report easily occurs to eliminate generation androstane -3,5,
16- triolefin -17- triflate accessory substances, influence product purity and yield and it is difficult to purifying, product must carry out column chromatography point
From complex operation is not suitable for industry's enlarging production；Trifluoromethanesulfanhydride anhydride is poisonous.
Route 2 obtains dehydrobenzene -17- hydrazones, then iodo shape with hydration hydrazine reaction first using dehydrobenzene as raw material
Into the iodo- androstane -5,16- diene -3 of 17-2-ol, and then abiraterone is made with the reaction of diethyl (3- pyridine radicals) borine, finally
Esterification is obtained, and total recovery is 41.5%.
Route 2 has the disadvantages that：Diethyl (3- pyridine radicals) borine and triphenylphosphine palladium chloride used in the reaction
Expensive, industrially cost is higher during a large amount of productions；Pillar layer separation is needed in course of reaction, is not suitable for extensive raw
Production；In synthetic route during prepare compound 6, document hydrazine sulfate needs 3d to complete as catalyst, reaction, and the reaction time is longer,
Requirement to reaction vessel is higher, and energy consumption is higher, influences the industrialization effect of the technique.
Domestic patent application（CN101044155, CN102816200, CN102816201 and CN102731605）Do not changing
On the premise of idiotoxin material and process route, in the proportioning fed intake, the use of catalyst, the selection of solvent, the control of condition
And be optimized and improve in terms of the method for purifying, make the technique more practical and perfect.
In addition, patent application CN102627681 and CN102838649 are using 17- iodo dehydrobenzene acetates
Beginning thing is condensed with 3- pyridines zinc halide or 3- halogens pyridine under catalyst action with 17- iodos dehydrobenzene, then through acetyl
Change the method that Abiraterone acetate is made.
Patent application CN102898495 and CN103059091 report one kind using dehydroepiandros-sterone as raw material, protect first
3 hydroxyls, then occur grignard reaction using RMgBr and the dehydrobenzene of 3 protections, then through dehydration and 3 remove-insurances
Shield, then the method through acylation reaction generation target product.
Foregoing disclosed document, mainly using dehydroepiandros-sterone as raw material, utilizes the dehydroepiandros-sterone trifluoro of 17-
The derivative of methanesulfonates (OTf) or iodo derivative and 3- bromopyridines（Ethyl borine, zincon and the grignard of 3 substitutions
Thing）Reaction obtains Abiraterone acetate.However, the conventional preparation method of dehydroepiandros-sterone is mainly using Chinese yam saponin as original at present
It is prepared by material.First, this production process needs substantial amounts of sulfuric acid, and a large amount of pollutions are easily produced to environment；Second, with China's ring
The continuous improvement of consciousness is protected, in recent years, country increases the environmentally friendly supervision to production of saponin enterprise, has eliminated part medium and small
Production of saponin enterprise, saponin supply is becoming tight, and has caused saponin price continuous rise since 2007, per ton 13 at the beginning of 2007
Ten thousand yuan go up more than 90 ten thousand yuan per ton to 2012.With the raising of saponin price, the price of dehydroepiandros-sterone also increases quickly；The
Three, the plantation of Chinese yam saponin needs largely prolonged land occupation.Therefore, new natural resources are developed, find a kind of alternative
The raw material of dehydroepiandros-sterone, can prepare Abiraterone acetate with lower cost and more environmentally-friendly method has important meaning
Justice.
In addition, the preparation method of the Abiraterone acetate involved by presently disclosed document report, although in reaction successively
Sequentially, it is optimized and improves on coupling reaction catalyst, the selection of 3- pyridine base side chains and activation method, but these are closed
Into route deficiency is still suffered from terms of production cost, reaction yield and three waste discharge.
The content of the invention
The technical problems to be solved by the invention are to provide the Abiraterone acetate that a kind of yield is high, reaction condition is gentle
Preparation method.
In order to solve the above technical problems, the technical solution adopted by the present invention is as follows：
A kind of synthetic method of Abiraterone acetate, it is characterised in that the synthetic method comprises the following steps：
Step one：Compound 1 generates compound 2, the catalyst choosing with triethyl orthoformate in the presence of catalyst
One or more from inorganic acid, organic acid and its pyridiniujm；
Step 2：With grignard reagent grignard reaction generation compound 3 occurs in the presence of catalyst for compound 2；It is described
Grignard reagent is 3- pyridine radicals magnesium bromides；
Step 3：Compound 3 reacts generation compound 4 with dehydrating agent in basic solvent；The basic solvent is selected from pyrrole
One or both of pyridine or triethylamine；
Step 4：Compound 4 is selected from aceticanhydride, acetyl with acetylation reagent reaction generation compound 5, the acetylation reagent
One or more in chlorine or methylvinyl acetate；
Step 5：Compound 5 obtains compound 6 with reducing agent reaction；
Step 6：Compound 6 is selected from vinegar with acetylation reagent reaction generation Abiraterone acetate, the acetylation reagent
One or more in acid anhydride, chloroacetic chloride.
A kind of synthetic method of described Abiraterone acetate, it is characterised in that：
Step one：Compound 1 generates compound 2, the catalyst choosing with triethyl orthoformate in the presence of catalyst
One or more from inorganic acid or organic acid and its pyridiniujm；
Step 2：With grignard reagent grignard reaction generation compound 3 occurs in the presence of catalyst for compound 2, described
Grignard reagent is 3- pyridine radicals magnesium bromides, and the catalyst is selected from cupprous inorganic salts；
Step 3：Compound 3 reacts generation compound 4 with dehydrating agent in basic solvent；The basic solvent is selected from pyrrole
One or both of pyridine or triethylamine；The dehydrating agent is selected from POCl3, mesyl chloride or to one in tosylate chloride
Plant or a variety of；
Step 4：Compound 4 is selected from aceticanhydride, acetyl with acetylation reagent reaction generation compound 5, the acetylation reagent
One or more in chlorine or methylvinyl acetate；
Step 5：Compound 5 obtains compound 6 with reducing agent reaction, and the reducing agent is selected from sodium borohydride, potassium borohydride
Or lithium aluminium hydride reduction；
Step 6：Compound 6 generates Abiraterone acetate, the second in the presence of acid binding agent with acetylation reagent reaction
One or more of the acylating reagent in aceticanhydride, chloroacetic chloride, the acid binding agent is selected from pyridine, triethylamine or 4- dimethylamino pyrroles
One or more in pyridine.
A kind of synthetic method of described Abiraterone acetate, it is characterised in that：
Step one：Reaction temperature is 0~60 DEG C；Solvent for use is in dioxane, tetrahydrofuran or absolute ethyl alcohol
It is one or more；
Step 2：Compound 2 in the presence of catalyst, is stirred 30 minutes with grignard reagent first at -20 DEG C~0 DEG C
~2 hours, then rise 15~30 DEG C and terminate to reaction, the catalyst is selected from stannous chloride or cuprous iodide；
Step 3：Reaction temperature is 25~120 DEG C；
Step 4：Reaction temperature is 20~100 DEG C；
Step 5：Reaction temperature is -20~100 DEG C；Solvent for use be selected from tetrahydrofuran, methanol, ethanol, dioxane,
One or more in N,N-dimethylformamide or the aqueous solution selected from above-mentioned solvent；
Step 6：Reaction temperature is 20~60 DEG C.
A kind of synthetic method of described Abiraterone acetate, it is characterised in that：
Step one：Reaction temperature is 20~40 DEG C；
Step 2：Compound 2 in the presence of catalyst, is stirred 30 minutes with grignard reagent first at -10 DEG C~0 DEG C
~2 hours, then rise 20~25 DEG C and terminate to reaction, the catalyst is selected from stannous chloride or cuprous iodide；
Step 3：Reaction temperature is 70~90 DEG C；
Step 4：Reaction temperature is 20~100 DEG C；
Step 5：Reaction temperature is 0~25 DEG C；
Step 6：Reaction temperature is 20~30 DEG C.
The compound of formula 1
The advantage of the present invention：
1. the present invention is using 4AD as raw material, cost is low.AD (abbreviation 4AD), utilizes soybean extract oil
Leftover bits and pieces afterwards --- phytosterol by bioanalysis fermentation obtains, compared with now widely used dehydroepiandros-sterone, 4AD and
ADD raw materials are based on industrial waste, and source more horn of plenty is consolidated, and price is cheaper, and very little is polluted in production process, be it is a kind of very
Advantageous raw material.Meanwhile, 4AD the and ADD purity and yield prepared with biological fermentation process is all very high, is conducive to improving steroidal medicine
The quality of thing finished product.Current 4AD price is about 700 yuan/kg, and the price of dehydroepiandros-sterone is about 2400~2600 yuan/kg.
2. high income, raw material is easy to get, no expensive reaction reagent, cost is low.
3. feasibility is high, strong operability, the Abiraterone acetate of high-purity can be just prepared by simply recrystallizing, it is easy to
Industrialization.
Embodiment：
Below will by embodiment, the invention will be further described, these description be not present invention is made into
The restriction of one step.Person skilled should be understood that the equivalent substitution made to the technical characteristic of the present invention, or be correspondingly improved,
Still fall within protection scope of the present invention.
TLC：Thin-layer chromatography
The synthesis of the compound 2 of embodiment one
Embodiment 1-1
Be passed through successively in there-necked flask nitrogen, input 20g compounds 1,40ml tetrahydrofurans, 20ml triethyl orthoformates,
0.2g p-methyl benzenesulfonic acid, reacts 3 hours under stirring in 20 DEG C, after TLC detection reactions substantially completely, adds in 0.2ml triethylamines
It is diluted in after in 1000ml frozen water.After filtering and discharging, in draining to obtain 22g compounds 2 under 30 DEG C of vacuum（Content 99%）.
Embodiment 1-2
Nitrogen, input 100g compounds 1,100ml absolute ethyl alcohols, 100ml primitive nail triethylenetetraminehexaacetic acids are passed through in there-necked flask successively
Ester is simultaneously passed through 1g hydrogen chloride gas, is reacted 3 hours in 40 DEG C under stirring, after TLC detection reactions substantially completely, adds the second of 2ml tri-
Amine is diluted in 5000ml frozen water after neutralizing.After filtering and discharging, in draining to obtain 108g compounds 2 under 30 DEG C of vacuum（Content 98%）.
Embodiment 1-3
Be passed through successively in there-necked flask nitrogen, input 20g compounds 1,40ml dioxane, 20ml triethyl orthoformates,
0.2g pyridine hydrochlorides, react 24 hours under stirring in 0 DEG C, after TLC detection reactions substantially completely, add in 0.2ml triethylamines
It is diluted in after in 1000ml frozen water.After filtering and discharging, in draining to obtain 21.3g compounds 2 under 30 DEG C of vacuum（Content 97%）.
Embodiment 1-4
Nitrogen, input 20g compounds 1,20ml absolute ethyl alcohols, 20ml tetrahydrofurans, 20ml are passed through in there-necked flask successively
Triethyl orthoformate, 0.2ml glacial acetic acid, 0.2ml formic acid, react 2 hours under stirring in 60 DEG C, and TLC detections reaction is substantially completely
Afterwards, add after 0.4ml triethylamines are neutralized and be diluted in 1000ml frozen water.After filtering and discharging, in draining to obtain 20.9g under 30 DEG C of vacuum
Compound 2（Content 95%）.
The synthesis of the compound 3 of embodiment two
Embodiment 2-1
The configuration of RMgBr：Magnesium chips 27g, 3- bromopyridine 92ml is added in 1000ml anhydrous tetrahydro furans, backflow is anti-
Answer after 4 hours, be cooled to -10 DEG C.
0.1g stannous chlorides are added in the above-mentioned RMgBr prepared, lead to nitrogen, then by the 40ml of 20g compounds 2
Tetrahydrofuran solution is slowly dropped in above-mentioned RMgBr, after completion of dropping, the insulation reaction 1h at -10 DEG C.Then it is slow
20 DEG C are risen to, stirring reaction 10 hours at 20 DEG C.TLC is diluted in water after having reacted, and concentrated hydrochloric acid regulation PH is 3 or so.Water
It is extracted twice with each 200ml ethyl acetate, combined ethyl acetate layer, each 150ml water washings ethyl acetate layer is twice, dense
After contracting dry ethyl acetate, recrystallizing methanol obtains 10g compounds 3（Content 95%）.8.8g, content are obtained with recrystallizing methanol again
99.5% compound 3.
Compound 3：m/e:365.21(100.0%)；Elementary analysis：C,78.84;H,8.57;N,3.82;C13NMR:
Embodiment 2-2
The configuration of RMgBr：Magnesium chips 27g, 3- bromopyridine 92ml is added in 1000ml anhydrous tetrahydro furans, backflow is anti-
Answer after 4 hours, be cooled to -20 DEG C.
0.1g cuprous iodides are added in the above-mentioned RMgBr prepared, lead to nitrogen, then by the 40ml of 20g compounds 2
Toluene solution is slowly dropped in above-mentioned RMgBr, after completion of dropping, the insulation reaction 0.5h at -20 DEG C.Then it is slow to rise
To 25~30 DEG C, stirring reaction 10 hours at 25~30 DEG C.It is diluted in after TLC detection reactions completely in water, concentrated hydrochloric acid is adjusted
It is 3 or so to save PH.Aqueous phase is extracted twice with each 200ml ethyl acetate, combined ethyl acetate layer, each 150ml water washings second
Twice, after concentration dry ethyl acetate, recrystallizing methanol obtains 10.2g compounds 3 to ethyl acetate layer（Content 96%）.
Embodiment 2-3
The configuration of RMgBr：Magnesium chips 27g, 3- bromopyridine 92ml is added in 1000ml anhydrous tetrahydro furans, backflow is anti-
Answer after 4 hours, be cooled to 0 DEG C.
0.1g stannous chlorides are added in the above-mentioned RMgBr prepared, lead to nitrogen, then by the 40ml of 20g compounds 2
Benzole soln is slowly dropped in above-mentioned RMgBr, after completion of dropping, the insulation reaction 2h at 0 DEG C.Then 15 DEG C are slowly increased to,
Stirring reaction 10 hours at 15 DEG C.It is diluted in after TLC detection reactions completely in water, concentrated hydrochloric acid regulation PH is 3 or so.Aqueous phase
It is extracted twice with each 200ml ethyl acetate, combined ethyl acetate layer, each 150ml water washings ethyl acetate layer twice, is concentrated
After dry ethyl acetate, recrystallizing methanol obtains 10.8g compounds 3（Content 95%）.
The synthesis of the compound 4 of embodiment three
Embodiment 3-1
10g compounds 3 are dissolved in the in the mixed solvent of 60ml pyridines and 20ml triethylamines, 9ml tolysulfonyl is added dropwise to
Chlorine, reaction solution is heated to 70 DEG C of clock reactions 10 hours, after be diluted in 800ml frozen water.Filtering and discharging after placing two hours, is obtained
7.4g compounds 4（Content 85%）.
Embodiment 3-2
10g compounds 3 are dissolved in 80ml pyridines, 4ml paratoluensulfonyl chlorides and 5ml POCl3s, reaction solution is added dropwise to
Be heated to 120 DEG C of clock reactions 7 hours, after be diluted in 800ml frozen water.Filtering and discharging after placing two hours, obtains 7.0g chemical combination
Thing 4（Content 83%）.
Embodiment 3-3
10g compounds 3 are dissolved in the in the mixed solvent of 20ml pyridines and 60ml triethylamines, 9ml mesyl chlorides are added dropwise to, instead
Answer liquid to be heated to 25 DEG C of clock reactions 24 hours, after be diluted in 800ml frozen water.Filtering and discharging after placing two hours, obtains 7.5g
Compound 4（Content 85%）.
Embodiment 3-4
By 10g compounds 3, it is dissolved in 80ml pyridines, is added dropwise to 9ml POCl3s, it is anti-that reaction solution is heated to 80 DEG C of timing
Answer 10 hours, after be diluted in 800ml frozen water.Filtering and discharging after placing two hours, obtains 7.4g compounds 4（Content 86%）.
Embodiment 3-5
By 10g compounds 3, it is dissolved in 80ml triethylamines, is added dropwise to 4ml POCl3s and 5ml mesyl chlorides, reaction solution adds
Heat to 90 DEG C of clock reactions 10 hours, after be diluted in 800ml frozen water.Filtering and discharging after placing two hours, obtains 7.3g compounds 4
（Content 84%）.
The synthesis of example IV compound 5
Embodiment 4-1
10g compounds 4,300ml aceticanhydrides, 6g p-methyl benzenesulfonic acid are added in reaction bulb, lead to nitrogen, in 20~25 DEG C of reactions
6 hours, after TLC detection reactions completely, 0 DEG C is cooled to, filtering, filter cake is diluted in 500ml frozen water, carried with ethyl acetate
Take, ethyl acetate washed with water is washed till after neutrality, be concentrated under reduced pressure after precipitation crystallization, be cooled to 0 DEG C, filtering and discharging, dry 11g
Compound 5（Content 89%）.
Embodiment 4-2
By in 10g compounds 4,20ml aceticanhydrides, in 25ml chloroacetic chlorides addition reaction bulb, lead to nitrogen, 6 are reacted in 70~75 DEG C
Hour, after TLC detection reactions completely, 0 DEG C is cooled to, filtering, filter cake is diluted in 500ml frozen water, extracted with ethyl acetate,
Ethyl acetate washed with water is washed till after neutrality, is concentrated under reduced pressure after precipitation crystallization, is cooled to 0 DEG C, filtering and discharging, dry 11gization
Compound 5（Content 93%）.
Embodiment 4-3
By in 10g compounds 4,50ml methylvinyl acetates, in 6g p-methyl benzenesulfonic acid addition reaction bulb, lead to nitrogen, in 95
~100 DEG C are reacted 2 hours, after TLC detection reactions completely, are cooled to 0 DEG C, filtering, filter cake is diluted in 500ml frozen water, are used
Ethyl acetate is extracted, and ethyl acetate washed with water is washed till after neutrality, is concentrated under reduced pressure after precipitation crystallization, is cooled to 0 DEG C, filters out
Material, dry 11g compounds 5（Content 85%）.
The synthesis of the compound 6 of embodiment five
Embodiment 5-1
10g compounds 5,100ml90% ethanol water, stirring, point 3 addition sodium borohydrides are added in toward reaction bulb
4g, every 10 minutes once.20~25 DEG C are reacted 12 hours, are cooled to 0 DEG C after TLC detection reactions completely, are adjusted with 50% acetic acid
PH is 7.It is diluted in 1000ml frozen water, is filtered after standing 2 hours, massive laundering, oven dried obtains 8g compounds 6（Content
80%）.
Embodiment 5-2
Toward adding 10g compound 5,100ml DMF in reaction bulb, stirring adds lithium aluminium hydride 4g, every 10 minutes points for 3 times
Once.95~100 DEG C are reacted 2 hours, and 0 DEG C is cooled to after TLC detection reactions completely, are 7 with 50% acetic acid regulation PH.Dilution
In 1000ml frozen water, filtered after standing 2 hours, massive laundering, oven dried obtains 8g compounds 6（Content 79%）.
Embodiment 5-3
10g compounds 5,100ml dioxane, 50ml methanol, stirring, point 3 addition hydroborations are added in toward reaction bulb
Potassium 4g, every 10 minutes once.0~5 DEG C is reacted 24 hours, is cooled to 0 DEG C after TLC detection reactions completely, is adjusted with 50% acetic acid
PH is 7.It is diluted in 1000ml frozen water, is filtered after standing 2 hours, massive laundering, oven dried obtains 8.1g compounds 6（Content
80%）.
Embodiment 5-4
Toward adding 10g compounds 5,100mlTHF in reaction bulb, stirring adds potassium borohydride 4g, every 10 minutes one points for 3 times
It is secondary.- 20~-15 DEG C are reacted 36 hours, and 0 DEG C is cooled to after TLC detection reactions completely, are 7 with 50% acetic acid regulation PH.Dilution
In 1000ml frozen water, filtered after standing 2 hours, massive laundering, oven dried obtains 7.9g compounds 6（Content 80%）.
The synthesis of the compound Abiraterone acetate of embodiment six
Embodiment 6-1
9g compounds 6,9ml aceticanhydrides, 45ml pyridines, DMAP 1.8g, 20 DEG C of stirrings 5 are added in toward reaction bulb
After hour, it is diluted in after TLC detection reactions completely in 700ml frozen water.After placing 2 hours, filtering and discharging is dried, and obtains 9.9g
Abiraterone acetate（Content 82%）.
Embodiment 6-2
Stirred 2 hours toward the interior addition 9g compounds 6 of reaction bulb, 5ml aceticanhydrides, 5ml chloroacetic chlorides, 45ml pyridines, 55~60 DEG C
Afterwards, it is diluted in after TLC detections reaction completely in 700ml frozen water.After placing 2 hours, filtering and discharging is dried, and obtains 9.9g acetic acid
Abiraterone（Content 81%）.
Embodiment 6-3
9g compounds 6,9ml chloroacetic chlorides, 45ml triethylamines are added in toward reaction bulb, after 30 DEG C are stirred 5 hours, TLC detections
It is diluted in after reaction completely in 700ml frozen water.After placing 2 hours, filtering and discharging is dried, and obtains 9.8g Abiraterone acetates（Contain
Amount 80%）.
The Abiraterone acetate of embodiment seven it is refined
Embodiment 7-1
By the Abiraterone acetate crude product of 10g contents 80% obtained with re-crystallizing in ethyl acetate 7.5g contents 99.6% acetic acid Ah
Bit dragon fine work.
Embodiment 7-2
The Abiraterone acetate crude product of 10g contents 80% is obtained into the acetic acid Ah's bit of 7.6g contents 99.5% with recrystallized from acetonitrile
Imperial fine work.
Embodiment 7-3
The Abiraterone acetate crude product of 10g contents 80% is obtained into the acetic acid Ah's bit of 7.5g contents 99.5% with recrystallizing methanol
Imperial fine work.
Claims (4)
1. a kind of synthetic method of Abiraterone acetate, it is characterised in that the synthetic method comprises the following steps：
Step one：Compound 1 generates compound 2 with triethyl orthoformate in the presence of catalyst, and the catalyst is selected from nothing
One or more in machine acid, organic acid and its pyridiniujm；Reaction temperature is 0~60 DEG C；
Step 2：With RMgBr grignard reaction generation compound 3 occurs in the presence of catalyst for compound 2；The lattice
Family name's reagent is 3- pyridine radicals magnesium bromides, and the catalyst is selected from cupprous inorganic salts, is reacted first at -20 DEG C~0 DEG C,
Then heat to 15~30 DEG C of reactions；
Step 3：Compound 3 reacts generation compound 4 with dehydrating agent in basic solvent；The basic solvent is selected from pyridine
One or both of or triethylamine；The dehydrating agent is selected from POCl3, mesyl chloride or to one kind in tosylate chloride
Or it is a variety of；Reaction temperature is 25~120 DEG C；
Step 4：Compound 4 is selected from aceticanhydride, chloroacetic chloride with acetylation reagent reaction generation compound 5, the acetylation reagent
Or the one or more in methylvinyl acetate；Reaction temperature is 20~100 DEG C；
Step 5：Compound 5 obtains compound 6 with reducing agent reaction；The reducing agent be selected from sodium borohydride, potassium borohydride or
Person's lithium aluminium hydride reduction；Reaction temperature is -20~100 DEG C；
Step 6：Compound 6 generates Abiraterone acetate, the acetyl in the presence of acid binding agent with acetylation reagent reaction
Change one or more of the reagent in aceticanhydride, chloroacetic chloride, the acid binding agent is selected from pyridine, triethylamine or 4- dimethylamino pyrroles
One or more in pyridine, reaction temperature is 20~60 DEG C.
2. the synthetic method of a kind of Abiraterone acetate as described in claim 1, it is characterised in that therein：
Step one：One or more of the solvent for use in dioxane, tetrahydrofuran or absolute ethyl alcohol；
Step 2：Compound 2 and RMgBr in the presence of catalyst, first at -20 DEG C~0 DEG C stirring 30 minutes~
2 hours, then heat to 15~30 DEG C and terminate to reaction, the catalyst is selected from stannous chloride or cuprous iodide；
Step 5：Solvent for use is selected from one kind in tetrahydrofuran, methanol, ethanol, dioxane, N, N- dimethylformamides
Or the aqueous solution a variety of or selected from above-mentioned solvent.
3. a kind of synthetic method of Abiraterone acetate as described in claim 2, it is characterised in that
Step one：Reaction temperature is 20~40 DEG C；
Step 2：Compound 2 in the presence of catalyst, is stirred 30 minutes with RMgBr first at -10 DEG C~0 DEG C
~2 hours, then heat to 20~25 DEG C and terminate to reaction, the catalyst is selected from stannous chloride or cuprous iodide；
Step 3：Reaction temperature is 70~90 DEG C；
Step 4：Reaction temperature is 20~100 DEG C；
Step 5：Reaction temperature is 0~25 DEG C；
Step 6：Reaction temperature is 20~30 DEG C.
4. the compound shown in following structure
。
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| CN101659976A (en) * | 2008-08-25 | 2010-03-03 | 天津金耀集团有限公司 | Method for preparing androstane-1,4,6-triene-3,17-diketone |
| WO2012083112A2 (en) * | 2010-12-16 | 2012-06-21 | Biomarin Pharmaceutical Inc. | Cyp11b, cyp17, and/or cyp21 inhibitors |
| CN102898495B (en) * | 2012-11-12 | 2014-11-26 | 浙江神洲药业有限公司 | Method for preparing abiraterone acetate |
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