CN103193849B - A kind of preparation method of high-purity Abiraterone acetate - Google Patents

A kind of preparation method of high-purity Abiraterone acetate Download PDF

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CN103193849B
CN103193849B CN201210009696.5A CN201210009696A CN103193849B CN 103193849 B CN103193849 B CN 103193849B CN 201210009696 A CN201210009696 A CN 201210009696A CN 103193849 B CN103193849 B CN 103193849B
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acetate
abiraterone
inorganic base
preparation
compound
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CN103193849A (en
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郭猛
王�华
张喜全
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Lianyungang Runzhong Pharmaceutical Co Ltd
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Lianyungang Runzhong Pharmaceutical Co Ltd
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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

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Abstract

The present invention relates to a kind of preparation method of high-purity Abiraterone acetate; the present invention by carrying out sulfonylation by Dehydroepiandrosterone Acetate and trifluoromethanesulfanhydride anhydride under the existence of inorganic base; the yield of Abiraterone acetate is significantly improved; accessory substance greatly reduces; and cost is low; there is no special smell or strong smell, easy operating, is particularly suitable for industrialized production.

Description

A kind of preparation method of high-purity Abiraterone acetate
Technical field
The present invention relates to a kind of technical field of process for preparing medicine, be specifically related to a kind of Abiraterone acetate withAnd the preparation method of intermediate.
Background technology
Abiraterone acetate is the synthetic middle key enzyme 17 α-hydroxylase-C17 of male sex hormone, and 20-lyase (also onceBe called steroid 17 α-monooxygenase inhibitor or human-cytochrome P45017α) effective selectivity oral press downPreparation, can be used for treating prostate cancer. On April 28th, 2011, FDA approval Abiraterone acetate is combined bold and vigorousBefore the treatment of Buddhist nun pine, used the metastatic castration resistance prostate cancer of docetaxel patients undergoing chemotherapy. Acetic acid Ah ratioThe chemical name of special dragon is (3 β)-17-(3-pyridine radicals)-androstane-5,16-dien-3-ols acetate, structural formulaAs follows:
The existing prior art of the synthetic method of Abiraterone acetate open (WO9320097, WO9509178,J.Med.Chem，1995，Vo38(13)，2463-2471，Org.Prep.Proced.Int.，1997，29(1)，123-134)，The wherein synthetic method described in WO9320097 and J.Med.Chem, taking Dehydroepiandrosterone Acetate as initiation material,With TFMS anhydride reactant, then carry out Suzuki coupling reaction with diethyl (3-pyridine radicals) borine and obtain acetic acidAbiraterone, reaction scheme is as follows.
WO9509178 and Org.Prep.Proced. are optimized said method. But in above documentThe method providing all can produce the more impurity that is difficult to remove, and impurity polarity and product are very approaching, even logicalPost is also difficult that impurity is removed, gained Abiraterone acetate not only purity is not high, yield is also low, operates numerousTrivial, be also not suitable for industrialized production.
Prepare Abiraterone acetate intermediate (IV) in method described in use WO9320097 and J.Med.ChemProcess in, by formula (III) compound under the existence of 2,6-di-t-butyl-4-picoline (DTBMP)Obtain Abiraterone acetate intermediate (IV) with TFMS anhydride reactant, this reaction can produce more formula (III)Eliminate product for 3 of compound, and feed stock conversion is lower, the DTBMP using very expensive simultaneously.
Consider and have above-mentioned shortcoming, CN101044155 replaces the alkaline reagent DTBMP of above-mentioned useChange, used tertiary amine or heterocyclic amine instead, wherein most preferred alkaline reagent is 2,6-lutidines or triethylamine.By above-mentioned improvement, though reduced cost, feed stock conversion also increases, and still exists yield lower,Problems such as accessory substance is many, and organic base also can generation make us very offending smell, wherein 2,6-dimethylPyridine has special smell, and triethylamine also has strong ammonia smelly, is unfavorable for industrialized production.
For fear of crossing post purifying Abiraterone acetate, CN101044155 and CN102030798 disclose respectivelyA kind of purification process is by dissociating and obtain Abiraterone acetate again after Abiraterone acetate crude product salify.Abiraterone acetate salt is separated out to rear filtration from solvent, can make most impurity stay in solution, soThe rear Abiraterone acetate that further dissociates to obtain. Although the method for this salify has avoided crossing post purifying,When the methanesulfonic acid salify of CN101044155, form the suspension of stiff, be difficult to filter, filter the filter cake obtaining stickyThick, easily residual impurity, purity is about 89%, purity is not high, wherein obviously contain pigment material, raw material,The impurity such as hydrolysate abiraterone. The TFMS using in CN102030798 is expensive, easily produces acidMist, also has severe corrosive, serious to equipment corrosion, and post processing and production operation difficulty are large, air pollutionSeriously, be therefore not suitable for industrialized production.
Summary of the invention
The present invention relates to the preparation method of a kind of compound (IV),
The method is that Dehydroepiandrosterone Acetate (III) and trifluoromethanesulfanhydride anhydride are carried out to sulfonylationCompound (IV), is characterized in that reacting under the existence of inorganic base.
Wherein, inorganic base comprises alkali metal hydroxide, alkali carbonate, alkali metal hydrogencarbonate, alkaliMetal phosphate, preferably NaOH, potassium hydroxide, lithium hydroxide, sodium carbonate, potash, bicarbonateSodium, saleratus, most preferably sodium carbonate, sodium acid carbonate.
The consumption of inorganic base is 2～10 times (mol ratios) of formula (III) compound, preferably 3～8 times, morePreferably 4～6 times.
This reaction is carried out in organic solvent, the organic solvent using comprise carrene, toluene, chloroform,Benzene, dimethylbenzene, preferably carrene, toluene, consumption be 3～30 times of formula (III) compound (volume/Mass ratio), preferably 5～15 times.
The consumption of trifluoromethanesulfanhydride anhydride is 0.7～2 times (mol ratio) of formula (III) compound, preferably 1～1.5Doubly.
This reaction temperature is-30 DEG C～30 DEG C.
The invention still further relates to compound (IV) that said method prepares as intermediate for the preparation of acetic acidThe purposes of abiraterone.
The preparation method who the invention still further relates to a kind of Abiraterone acetate crude product, the method comprises the following steps:
(1) Dehydroepiandrosterone Acetate (III) and trifluoromethanesulfanhydride anhydride carry out sulfonylation and obtain under the existence of inorganic baseCompound (IV);
(2) compound (IV) and diethyl (3-pyridine radicals) borine carry out Suzuki coupling reaction and obtain Abiraterone acetate(I) crude product.
Wherein step (2) can adopt known method to carry out, as disclosed method in WO9320097.
The invention still further relates to a kind of purification process of Abiraterone acetate, the method is by Abiraterone acetate (I)The crude product reaction that is hydrolyzed under alkali condition, obtain abiraterone (II), then by abiraterone (II)Carry out acetylization reaction and obtain Abiraterone acetate (I).
Wherein, hydrolysing agent comprise NaOH, potassium hydroxide, lithium hydroxide, sodium carbonate, potash,Ammoniacal liquor, preferably NaOH, sodium carbonate; Every mole of formula (I) compound uses the hydrolysis of 0.5～2 moleReagent, preferably 0.8～1.2 mole. The solvent of the hydrolysis using is selected from a kind of or a kind of in followingAbove: methyl alcohol, ethanol, acetone, oxolane, water, the amount of solvent is 4～10 of formula (I) compoundDoubly (volume/mass ratio). Described acetylation reagent is chloroacetic chloride, acetic anhydride etc.; Every mole of formula (II)Compound uses the acetylation reagent of 1～5 mole, preferably 2～4 moles.
The invention still further relates to a kind of preparation method of high-purity Abiraterone acetate, the synthetic route of the method is:
The method comprises following reactions steps:
(1) Dehydroepiandrosterone Acetate (III) and trifluoromethanesulfanhydride anhydride carry out sulfonylation and obtain under the existence of inorganic baseCompound (IV);
(2) compound (IV) and diethyl (3-pyridine radicals) borine carry out Suzuki coupling reaction and obtain Abiraterone acetate(I) crude product;
(3) crude product of Abiraterone acetate (I) reaction that is hydrolyzed under alkali condition, filters, and obtains abiraterone (II)；
(4) abiraterone (II) carries out acetylization reaction and obtains Abiraterone acetate (I).
Wherein, in step (1), described inorganic base comprises alkali metal hydroxide, alkali carbonate, alkaliAlkali metal bicarbonate salt, alkali metal phosphate, preferably NaOH, potassium hydroxide, lithium hydroxide, sodium carbonate,Potash, sodium acid carbonate, saleratus, most preferably sodium carbonate, sodium acid carbonate. The consumption of inorganic base is formula(III) 2～10 of compound times (mol ratio), preferably 3～8 times, more preferably 4～6 times.
The described reaction of step (1) is carried out in organic solvent, the organic solvent that can use comprise carrene,Toluene, chloroform, benzene, dimethylbenzene, preferably carrene, toluene, consumption be 3 of formula (III) compound～30 times (volume/mass ratio), preferably 5～15 times.
The consumption of described trifluoromethanesulfanhydride anhydride is 0.7～2 times (mol ratio) of formula (III) compound, excellentSelect 1～1.5 times.
The reaction temperature of step (1) is-30 DEG C～30 DEG C.
In step (3), described hydrolysing agent comprise NaOH, potassium hydroxide, lithium hydroxide, sodium carbonate,Potash, ammoniacal liquor, preferably NaOH, sodium carbonate; Every mole of formula (I) compound uses 0.5～2 to rubYour hydrolysing agent, preferably 0.8～1.2 mole. The solvent of the hydrolysis that step (3) is used is selected from followingIn one or more: methyl alcohol, ethanol, acetone, oxolane, water, the amount of solvent is formula (I)4～10 times (volume/mass ratios) of compound.
In step (4), described acetylation reagent is chloroacetic chloride, acetic anhydride etc.; Every mole of formula (II) chemical combinationThing uses the acetylation reagent of 1～5 mole, preferably 2～4 moles.
As required, in step (4), the Abiraterone acetate of gained can further obtain more high-purity by recrystallizationThe Abiraterone acetate of degree, the solvent of recrystallization comprises ethanol, methyl alcohol, isopropyl alcohol etc., particular methanol.
It should be noted that and use purification process of the present invention, step (4) even in the Abiraterone acetate that obtainsNo longer be recrystallized, purity is also very high, reaches more than 99.6%, can meet needs prepared by product completely.Therefore the Abiraterone acetate, obtaining in step (4) does not preferably need to be recrystallized again.
First the present invention has improved the preparation method of the midbody compound (IV) of Abiraterone acetate in synthetic,By adopting solid inorganic alkali to replace the organic liquor such as DTBMP alkali or tertiary amine, heterocyclic amine using in prior artBody alkali, improves the yield of midbody compound (IV) greatly, and accessory substance greatly reduces, and then makes vinegarYield and the purity of acid abiraterone crude product also improve greatly, and the method cost is low, and do not have special smell orStrong smell, easy operating, is particularly suitable for industrialized production.
Again, the present invention obtains Abiraterone acetate crude product after by sulfonylation and coupling reaction,There is no the compound of gained in the above-mentioned any two-step reaction of purifying, after two-step reaction, do not use post to separateImpurity, does not also carry out this crude product of purifying by salify, and has been to provide a kind of brand-new purification process, the partyMethod is first hydrolyzed into abiraterone by Abiraterone acetate crude product, directly in reaction dissolvent, separates out abiraterone admittedlyBody, can remove the impurity of unreacted raw material and generation completely, makes afterwards by simple acetylization reactionAbiraterone acetate sterling. The Abiraterone acetate purity that this purification process obtains is high, and avoided cross post andThe troublesome operation of salify purifying, avoids the use of a large amount of solvents, and simple to operate, cost is low.
The present invention is by using inorganic base synthetic intermediate (IV) and being first hydrolyzed the purification process of acidylate again,The Abiraterone acetate purity preparing is very high, even if be no longer recrystallized, Abiraterone acetatePurity also can reach more than 99.6%. By method of the present invention, the product yield that obtains is high, purity is high, andAnd the method cost is low, good product quality, be white crystalline solid, technique is simple to operation, does not have badSmell is applicable to industrialized production very much.
Detailed description of the invention
The preparation of embodiment 1 compound (IV) and Abiraterone acetate crude product
(1) preparation of compound (IV)
N2Under protection, 1.5L carrene is cooled to after-10～-5 DEG C, under stirring, adds 150g acetic acid to goHydrogen meter androsterone (III), 7.5g dimethylamino naphthyridine (DMAP), 200gNa2CO3. Slowly drip Tf2O180g，1～1.5h drips off, and continues reaction 2～3h. With frozen water 1.5L cancellation, separatory, carrene for water (0.5L)Extraction, merges organic phase, 1.5L water washing 4 times, and anhydrous sodium sulfate drying, concentrates to obtain atropurpureus greaseAbout 203g compound (IV), yield 96.6%.
(2) preparation of Abiraterone acetate crude product
The above-mentioned formula IV compound (203g) preparing, THF (1.5L), Pd (PPh3)2Cl2(2.7g), twoEthyl-(3-pyridine) borine (72g) and 2MNa2CO3(0.75L). Be heated to 80 DEG C of outer temperature, reaction 4～5h.Leave standstill separatory, upper organic phase adds 2L ethyl acetate, with 2L water washing 4 times, anhydrous sodium sulfate drying.Revolve and steam to obtain 171g dark oil thing Abiraterone acetate crude product (I), total recovery 96.2% is (based on compound (III)Calculate), purity 93.8%.
High efficiency liquid phase (HPLC) condition that described purity detecting is used:
Chromatographic column: (4.6 × 150mm, 5 μ m) for kromasil100C18 post
Mobile phase: 75% methyl alcohol
Detect wavelength: 210nm
Column temperature: 30 DEG C
Flow velocity: 1ml/min.
Described yield is mol ratio percentage.
Embodiment 2～7: the preparation of compound (IV) and Abiraterone acetate crude product
In use table 1, each material and consumption obtain compound (IV) according to the method for embodiment 1 (1), then ginsengMethod according to embodiment 1 (2) obtains Abiraterone acetate crude product, and wherein the consumption of each material can be according to circumstancesSuitably adjust, the results are shown in Table 1.
Table 1:
The preparation method of embodiment 8 high-purity Abiraterone acetates
Prepare Abiraterone acetate crude product according to embodiment 1, get that embodiment 1 prepares acetic acid AhBit dragon crude product 100g, adds 400ml methyl alcohol, adds 10%NaOH aqueous solution 100ml under stirring, stirs4h, filters, and filter cake adds 500ml carrene heating for dissolving, 200ml washing 2 times, and concentrated carrene,50 DEG C of drying under reduced pressure 4h, obtain solid 78.5g (II).
Under room temperature, add 78.5g (II), carrene 500ml, triethylamine 35g, stir and slowly drip downChloroacetic chloride (with the mol ratio of compound (II) be 4 equivalents), in 1h, dropwise. Continue reaction 5h,Finish after reaction, add 200ml washing 3 times, organic phase anhydrous sodium sulfate drying, concentrated, 50 DEG C subtractPress dry dry 4h, obtain solid 81.6g (I), purity 99.8%.
The preparation method of embodiment 9～13 high-purity Abiraterone acetates
In use table 2, each material and consumption the method according to embodiment 8 are prepared high-purity Abiraterone acetate,The results are shown in Table 2.
Table 2
Embodiment 14: check experiment
React and obtain compound (IV) as sulfonylation agent with 2,6-lutidines, triethylamine respectively,Then prepare Abiraterone acetate crude product according to the method for (2) in embodiment 1, embodiment as a comparison,And compare with the embodiment of the present invention 1, the results are shown in Table 3.
Comparative example 1: be that sulfonylation agent is prepared compound IV with 2,6-lutidines
100g Dehydroepiandrosterone Acetate is added in 1L carrene, under stirring, adds 56mL fluoroform sulphurAcid anhydrides, solution after 5 minutes, added 33.1g2 in stirring at room temperature in 25 minutes, the 1L of 6-lutidinesDichloromethane solution, and in stirring at room temperature 3.5 hours, add 1.5L shrend to go out after reaction, multi_layer extraction,Water 750ml dichloromethane extraction, merges organic phase, and uses 750ml2NHCl solution washing, layeringSeparate, through anhydrous Na2SO4, dry and 70g charcoal treatment organic phase is after 10 minutes, suction filtration, filtrate subtractsPress the concentrated 120.5g brown oil that obtains. Then, prepare according to the method for (2) in embodiment 1Abiraterone acetate 96g, calculates total recovery (taking initiation material Dehydroepiandrosterone Acetate as benchmark), and measuresPurity.
Comparative example 2: prepare compound IV taking triethylamine as sulfonylation agent
To the 1LCH that is present in stirring2Cl2In Dehydroepiandrosterone Acetate (100g) solution in add Tf2O(56Ml), by this reactant in stirring at room temperature 5 minutes. Added and be stored in 1LCH through 25 minutes2Cl2Triethylamine(42.2ml) solution. By the purple solution obtaining in stirring at room temperature 3.5 hours. By adding water, 1.5L quencher shouldReactant, separates each layer. Use 0.75LCH2Cl2Aqueous layer extracted, merges organic layer. Use 2NHCl0.75LWith salt solution 0.75L washing organic moiety. Use MgSO4Process organic layer 10 minutes with active carbon 70g. Filter,Reduced pressure concentration leaches thing, obtains 118g brown oil. Then, according to the method for (2) in embodiment 1Prepare Abiraterone acetate 94.8g, calculate total recovery (taking initiation material Dehydroepiandrosterone Acetate as benchmark),And measure purity.
Table 3
Example Sulfonylation agent Compound (IV) yield Abiraterone acetate crude product total recovery Abiraterone acetate crude product purity
The embodiment of the present invention 1 Sodium carbonate 96.6％ 96.2％ 93.8％
Comparative example 1 2,6-lutidines 86.0％ 81.0％ 84.2％
Comparative example 2 Triethylamine 84.2％ 80.0％ 82.3％

Claims (10)

1. the preparation method of compound (IV),
The method is Dehydroepiandrosterone Acetate and trifluoromethanesulfanhydride anhydride to be carried out to sulfonylation obtain compound(IV), is characterized in that reacting under the existence of inorganic base, and described inorganic base is NaOH, hydrogenPotassium oxide, sodium carbonate, potash, sodium acid carbonate, saleratus.
2. preparation method claimed in claim 1, wherein inorganic base is sodium carbonate, sodium acid carbonate.
3. preparation method claimed in claim 1, wherein the consumption of inorganic base is Dehydroepiandrosterone Acetate 2～10Doubly.
4. preparation method claimed in claim 1, wherein the consumption of inorganic base is Dehydroepiandrosterone Acetate 3～8Doubly.
5. preparation method claimed in claim 1, wherein the consumption of inorganic base is Dehydroepiandrosterone Acetate 4～6Doubly.
6. a preparation method for Abiraterone acetate crude product, the method comprises the following steps:
(1) Dehydroepiandrosterone Acetate and trifluoromethanesulfanhydride anhydride carry out sulfonylation and obtain compound under the existence of inorganic base(IV), described inorganic base be NaOH, potassium hydroxide, sodium carbonate, potash, sodium acid carbonate,Saleratus;
(2) compound (IV) and diethyl (3-pyridine radicals) borine carry out Suzuki coupling reaction and obtain Abiraterone acetateCrude product;
Wherein, the structure of compound (IV) is
7. a preparation method for Abiraterone acetate, the method comprises following reactions steps:
(1) Dehydroepiandrosterone Acetate and trifluoromethanesulfanhydride anhydride carry out sulfonylation and obtain compound under the existence of inorganic base(IV), described inorganic base is NaOH, potassium hydroxide, sodium carbonate, potash, sodium acid carbonate, carbonPotassium hydrogen phthalate;
(2) compound (IV) and diethyl (3-pyridine radicals) borine carry out Suzuki coupling reaction and obtain Abiraterone acetateCrude product;
(3) the crude product of the Abiraterone acetate reaction that is hydrolyzed under alkali condition, filters, and obtains abiraterone;
(4) abiraterone carries out acetylization reaction and obtains Abiraterone acetate;
Wherein, the structure of compound (IV) is
8. method claimed in claim 7, the hydrolysing agent that wherein hydrolysis uses is NaOH, hydrogen-oxygenChange potassium, lithium hydroxide, sodium carbonate, potash, ammoniacal liquor.
9. method claimed in claim 7, the solvent that wherein hydrolysis uses be selected from methyl alcohol, ethanol, acetone,One or more in oxolane, water.
10. method claimed in claim 7, the acetylation reagent that wherein acetylization reaction uses for chloroacetic chloride,Acetic anhydride.
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CN103965282B (en) * 2014-04-21 2016-01-20 武汉百科药物开发有限公司 A kind of preparation method of Abiraterone acetate
CN105294806A (en) * 2014-06-13 2016-02-03 江苏希迪制药有限公司 Method for preparing abiraterone acetate intermediate
CN104370991B (en) * 2014-11-18 2016-04-27 仙居县力天化工有限公司 A kind of synthetic method of Abiraterone acetic ester
CN105713063A (en) * 2014-12-02 2016-06-29 重庆安格龙翔医药科技有限公司 Abiraterone acetate preparation method
CN107840866A (en) * 2016-09-20 2018-03-27 正大天晴药业集团股份有限公司 The preparation method of Abiraterone acetate
CN108586561B (en) * 2018-04-03 2020-08-04 科兴生物制药股份有限公司 Method for preparing abiraterone acetate
CN108794561A (en) * 2018-07-13 2018-11-13 徐州工业职业技术学院 A kind of Abiraterone acetate highly finished product synthetic method
CN108546279A (en) * 2018-07-16 2018-09-18 徐州工业职业技术学院 A kind of Abiraterone acetate highly finished product are raw materials used and its synthetic method
CN111349138B (en) * 2018-12-24 2023-06-16 江苏恒瑞医药股份有限公司 Method for preparing abiraterone acetate
CN112812147A (en) * 2019-11-15 2021-05-18 江苏佳尔科药业集团股份有限公司 Synthetic method of abiraterone acetate and intermediate thereof

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