CN107652294A - A kind of preparation method of Ibrutinib - Google Patents
A kind of preparation method of Ibrutinib Download PDFInfo
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- CN107652294A CN107652294A CN201711120491.3A CN201711120491A CN107652294A CN 107652294 A CN107652294 A CN 107652294A CN 201711120491 A CN201711120491 A CN 201711120491A CN 107652294 A CN107652294 A CN 107652294A
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- XMXLYEKPSHVLKD-UHFFFAOYSA-N COC(c(cc1)ccc1Oc1ccccc1)=O Chemical compound COC(c(cc1)ccc1Oc1ccccc1)=O XMXLYEKPSHVLKD-UHFFFAOYSA-N 0.000 description 2
- RYAQFHLUEMJOMF-UHFFFAOYSA-N OC(c(cc1)ccc1Oc1ccccc1)=O Chemical compound OC(c(cc1)ccc1Oc1ccccc1)=O RYAQFHLUEMJOMF-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Oc1ccccc1 Chemical compound Oc1ccccc1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
The invention discloses a kind of preparation method of Ibrutinib, comprise the following steps：(1) IB A preparation；(2) IB B preparation；(3) IB C preparation；(4) IB D preparation；(5) IB E preparation；(6) IB F preparation；(7) IB G preparation；(8) IB H preparation；(9) IB J preparation.The advantage of the invention is that：Technical maturity is stable, and product quality is stable, and production technology is safe and reliable.It is adapted to industrialized production.
Description
Technical field
The present invention relates to bulk drug and intermediate preparing technical field, more particularly to a kind of preparation method of Ibrutinib.
Background technology
Ibrutinib is the BTK inhibitor of Pharmacyclics/Johnson＆Johnson joint developments, this time through FDA
Breakthrough medicine, preferentially evaluate, accelerate approval, Orphan drug quadruple passage to ratify to be used for lymphoma mantle cell.In November, 2013 quilt
Treatment of the U.S. FDA approval listing available for lymphoma mantle cell (MCL), and extremely recurred with increase indication in 2014 and 2015
Or the preferred medication of intractable lymphoma mantle cell, chronic lymphatic leukemia and Waldenstrom's macroglobulinemia.At present among it
Body main exit India, the preparation method about Ibrutinib studies have reported that, U.S. Patent No. US20080108636,
No. US2008058528, No. US2009050897, No. US2010254905 and No. US2011039190 reports her
Replace the synthetic method of Buddhist nun and the like in Shandong.This method is using 4- phenoxy benzoic acids as raw material, by acylation, condensation, methoxyl group
The reactions such as change, pyrazoles cyclisation, pyrimidine cyclisation, N- alkylations, deprotection and allyl acylation, make functional group constantly cumulative, final system
Obtain target product.But the route steps are more, it is necessary to use a variety of unconventional raw materials and reagent, particularly trimethyl silicane diazonium first
Triphenylphosphine of alkane and macromolecule loading etc. has potential dangerous and environmental contamination, thus is unfavorable for industrializing.
World patent application the W02013003629th and Chinese Patent No. CN103121999 then report another kind and changed
The preparation method for the Ibrutinib entered, it, for raw material, leads to iodo or bromo respectively all with 1H- pyrazolos [3,4-d] pyrimidine -4- amine
Prepare iodo- 1H- pyrazolos [3, the 4-d] pyrimidine -4- amine of 3- or bromo- 1H- pyrazolos [3, the 4-d] pyrimidine -4- amine of 3-.The halo of gained
Thing obtains target product through Suzuki coupling reactions, Mitsunobu coupled reactions, deprotection and amidation process successively again.With
Original is ground reaction and compared, and the synthetic method step has been reduced, and total recovery increases.But due to without reference to female ring 1H- pyrazoles
And the preparation of [3,4-d] pyrimidine -4- amine, and preparation process will use the reactions such as halo, Suzuki couplings, Mitsunobu couplings,
So that manufacturing cost and reaction condition are undesirable.
The content of the invention
It is an object of the invention to provide a kind of preparation method of Ibrutinib, to solve what is proposed in above-mentioned background technology
Problem.
To achieve the above object, the present invention provides following technical scheme：A kind of preparation method of Ibrutinib, including it is as follows
Step：
(1) IB-A preparation
(2) IB-B preparation
(3) IB-C preparation
(4) IB-D preparation
(5) IB-E preparation
(6) IB-F preparation
(7) IB-G preparation
(8) prepared by IB-H
(9) IB-J preparation
One of preferred embodiment as the present invention, the specific preparation method in step (1) is：Under stirring at normal temperature, to IB-
Potassium carbonate, cuprous iodide are added in SM1 and IB-SM2 DMF solution, after charging terminates, reaction mixture
7-9 hours are stirred at 100-120 DEG C, be concentrated under reduced pressure recovery DMF, 800-900L water is added, with methyl- tert fourth
Base ether extracts, organic extract liquid washing, adds ethanol after reclaiming organic solvent, gained IB-A ethanol solutions are directly used in next step
Reaction.
One of preferred embodiment as the present invention, the specific preparation method in step (2) is：Under stirring at normal temperature, to IB-A
The aqueous solution of sodium hydroxide is added in ethanol solution, after charging terminates, reaction mixture stirs 1-2 hours at 60-80 DEG C, concentration
Ethanol is reclaimed, is cooled to less than 10 DEG C, below 10 DEG C plus 35-37% salt acid for adjusting pH value to 2-3, mixed liquor stirs at room temperature
2-3 hours are mixed, by the centrifugation of caused solid, dries, obtains white solid product IB-B.
One of preferred embodiment as the present invention, the specific preparation method in step (3) is：IB- is added into reactor
B, dichloromethane and thionyl chloride solution are stirred at reflux 11-13 hours at 30-50 DEG C, and be concentrated under reduced pressure recovery dichloromethane and chlorination
Sulfoxide, Liquid Residue add tetrahydrofuran, can be directly used for reaction in next step without being further purified.
One of preferred embodiment as the present invention, the specific preparation method in step (4) is：0-2 DEG C, under malononitrile
Diisopropylethylamine is added in dry tetrahydrofuran solution, after charging terminates, is warming up to and 1-2h is stirred at room temperature, be then cooled to 0-2
DEG C, IB-C dry tetrahydrofuran solution is slowly added into reaction mixture, after charging terminates, reaction mixture is at 0-2 DEG C
1-2 hours are stirred, water quenching is slowly added into and goes out reaction, after end is quenched, addition 14-16% aqueous ammonium chloride solutions, use ethyl acetate
Extraction, organic extracts washed with water and the washing of 15-25% salt, concentration organic solvent obtains Red oil crude product, with Isosorbide-5-Nitrae-two
The ring of oxygen six recrystallizes, and centrifugation, is dried to obtain solid product IB-D.
One of preferred embodiment as the present invention, the specific preparation method in step (5) is：Add IB-D into reactor,
Dioxane, potassium carbonate and dimethyl suflfate, after charging terminates, reaction mixture is heated to 70-90 DEG C, stirs 2-4 hours, subtracts
Concentration and recovery dioxane is pressed, water is added, is extracted with ethyl acetate, organic extracts washed with water washing, be concentrated under reduced pressure recovery acetic acid
Ethyl ester, crude product is obtained, with 1：1 normal heptane/re-crystallizing in ethyl acetate, centrifugation, drying obtain pale yellow solid product IB-E.
One of preferred embodiment as the present invention, the specific preparation method in step (6) is：IB-E is added to reactor,
80-90% hydrazine hydrates are added in ethanol solution, after charging terminates, reactant mixture is concentrated under reduced pressure in 80-100 DEG C of backflow 1-3h
Ethanol is reclaimed, water crystallization is added, centrifugation, is dried to obtain solid IB-F.
One of preferred embodiment as the present invention, the specific preparation method in step (7) is：Characterized in that, step (7)
In specific preparation method be：IB-F is added in reactor, formamide is added, under nitrogen protection, is heated to 170-190
DEG C, and 3-5h is stirred at 170-190 DEG C, reactant mixture is cooled to 20-40 DEG C, water is added and centrifuges to obtain solid, be used in combination
Methanol washs, and is dried to obtain IB-G.
One of preferred embodiment as the present invention, the specific preparation method in step (8) is：By IB-G, triphenylphosphine and
Tetrahydrofuran is added in reactor, and (S)-N-BOC-3- hydroxy piperidines are added after stirring, are subsequently added into azoformic acid diisopropyl
Ester, 7-9h is stirred at room temperature in reactant mixture, filters reactant mixture, resulting solution adds 15-25% brine Its 2
Time, organic phase concentration, crystallized with methyl tertiary butyl ether(MTBE), filter, be dried to obtain IB-H.
One of preferred embodiment as the present invention, the specific preparation method in step (9) is：IB-H is added into reactor
In, dioxane is added, hydrogen chloride gas is passed through at 0-2 DEG C, is warming up to 20-30 DEG C of stirring 1-2h, reaction solution concentration, residue
Dichloromethane dissolving is added, adds triethylamine, is then added dropwise and adds acrylic acyl chlorides, stop reaction, reactant mixture after 2-3 hours
Washed with 4-6% lemon rubber aqueous acids, then with salt water washing, organic layer concentration, the crystallization of methylate tertbutyl ether, filtering, obtained
The crude product arrived, 35-45 DEG C of dissolving is heated to after adding ethanol, adds activated carbon, 2-3h is stirred at 40-50 DEG C, passes through diatomite
Filter cake heat filtering, gained filtrate is cooled to 0-2 DEG C of crystallization, and filtration drying obtains IB-J.
Compared with prior art, the beneficial effects of the invention are as follows：Technical maturity is stable, and product quality is stable, production technology
Securely and reliably.It is adapted to industrialized production.
Embodiment
Technical scheme is described in more detail with reference to embodiment.
Embodiment 1
A kind of preparation method of Ibrutinib, comprises the following steps：
(1) IB-A preparation
Synthesis flow is as follows：
Preparation process：Under stirring at normal temperature, carbonic acid is added into IB-SM1 and IB-SM2 DMF solution
Potassium, cuprous iodide, after charging terminates, reaction mixture stirs 7 hours at 100 DEG C, and be concentrated under reduced pressure recovery N, N- dimethyl formyls
Amine, 800L water is added, is extracted with methyl tertiary butyl ether(MTBE), organic extract liquid washing, ethanol, gained are added after reclaiming organic solvent
IB-A ethanol solutions are directly used in react in next step.
(2) IB-B preparation
Synthesis flow is as follows：
Preparation process：Under stirring at normal temperature, the aqueous solution of sodium hydroxide is added into IB-A ethanol solutions, after charging terminates,
Reaction mixture stirs 1 hour at 60 DEG C, concentration and recovery ethanol, is cooled to 9 DEG C, in 9 DEG C plus 35% salt acid for adjusting pH value to 2,
Mixed liquor is stirred at room temperature 2 hours, by the centrifugation of caused solid, dries, obtains white solid product IB-B.
(3) IB-C preparation
Synthesis flow is as follows：
Preparation process：IB-B, dichloromethane and thionyl chloride solution are added into reactor, and at 30 DEG C to be stirred at reflux 11 small
When, be concentrated under reduced pressure recovery dichloromethane and thionyl chloride, and Liquid Residue adds tetrahydrofuran, can be directly used for reacting and nothing in next step
It need to be further purified.
(4) IB-D preparation
Synthesis flow is as follows：
Preparation process：At 0 DEG C, to malononitrile under add diisopropylethylamine in dry tetrahydrofuran solution, charging terminates
Afterwards, it is warming up to and 1h is stirred at room temperature, be then cooled to 0 DEG C, the dry tetrahydrofuran that IB-C is slowly added into reaction mixture is molten
Liquid, after charging terminates, reaction mixture stirs 1 hour at 0 DEG C, is slowly added into water quenching and goes out reaction, after end is quenched, addition 15%
Aqueous ammonium chloride solution, it is extracted with ethyl acetate, organic extracts washed with water and the washing of 15% salt, concentration organic solvent obtain red
Oily crude product, recrystallized with Isosorbide-5-Nitrae-dioxane, centrifugation, be dried to obtain solid product IB-D.
(5) IB-E preparation
Synthesis flow is as follows：
Preparation process：Add IB-D into reactor, dioxane, potassium carbonate and dimethyl suflfate, after charging terminates, react
Mixed liquor is heated to 70 DEG C, stirs 2 hours, and be concentrated under reduced pressure recovery dioxane, adds water, is extracted with ethyl acetate, You Jicui
Liquid is taken to be washed with water, be concentrated under reduced pressure recovery ethyl acetate, crude product is obtained, with 1：1 normal heptane/re-crystallizing in ethyl acetate, from
The heart, drying obtain pale yellow solid product IB-E.
(6) IB-F preparation
Synthesis flow is as follows：
Preparation process：IB-E is added to reactor, 80% hydrazine hydrate is added in ethanol solution, after charging terminates, reaction is mixed
In 80 DEG C of backflow 1h, be concentrated under reduced pressure compound recovery ethanol, adds water crystallization, centrifugation, is dried to obtain solid IB-F.
(7) IB-G preparation
Synthesis flow is as follows：
Preparation process：IB-F is added in reactor, adds formamide, under nitrogen protection, is heated to 170 DEG C, and
3h is stirred at 170 DEG C, reactant mixture is cooled to 20 DEG C, water is added and centrifuges to obtain solid, and is washed with methanol, dry
To IB-G.
(8) prepared by IB-H
Synthesis flow is as follows：
Preparation process：By IB-G, triphenylphosphine and tetrahydrofuran are added in reactor, and (S)-N-BOC-3- is added after stirring
Hydroxy piperidine, diisopropyl azodiformate is subsequently added into, 7h, filtering reaction mixing is stirred at room temperature in reactant mixture
Thing, resulting solution add 15% brine It 2 times, organic phase concentration, are crystallized with methyl tertiary butyl ether(MTBE), filter, be dried to obtain
IB-H。
(9) IB-J preparation
Synthesis flow is as follows：
Preparation process：IB-H is added in reactor, dioxane is added, is passed through hydrogen chloride gas at 0 DEG C, is warming up to 20
DEG C stirring 1h, reaction solution concentration, residue add dichloromethane dissolving, add triethylamine, then be added dropwise plus acrylic acyl chlorides, 2
Stop reaction after hour, reactant mixture is washed with 4% lemon rubber aqueous acid, then with salt water washing, organic layer concentration, adds first
Base tertbutyl ether crystallizes, filtering, obtained crude product, is heated to 35 DEG C of dissolvings after adding ethanol, adds activated carbon, continue at 40 DEG C
2h is stirred, by diatomaceous filter cake heat filtering, gained filtrate is cooled to 0 DEG C of crystallization, and filtration drying obtains IB-J.
Embodiment 2
A kind of preparation method of Ibrutinib, comprises the following steps：
(1) IB-A preparation
Synthesis flow is as follows：
Preparation process：Under stirring at normal temperature, carbonic acid is added into IB-SM1 and IB-SM2 DMF solution
Potassium, cuprous iodide, after charging terminates, reaction mixture stirs 8 hours at 110 DEG C, and be concentrated under reduced pressure recovery N, N- dimethyl formyls
Amine, 850L water is added, is extracted with methyl tertiary butyl ether(MTBE), organic extract liquid washing, ethanol, gained are added after reclaiming organic solvent
IB-A ethanol solutions are directly used in react in next step.
(2) IB-B preparation
Synthesis flow is as follows：
Preparation process：Under stirring at normal temperature, the aqueous solution of sodium hydroxide is added into IB-A ethanol solutions, after charging terminates,
Reaction mixture stirs 1.5 hours at 70 DEG C, concentration and recovery ethanol, is cooled to 8 DEG C, adds 36% salt acid for adjusting pH value extremely at 8 DEG C
2.5, mixed liquor is stirred at room temperature 2.5 hours, by the centrifugation of caused solid, dries, obtains white solid product IB-B.
(3) IB-C preparation
Synthesis flow is as follows：
Preparation process：IB-B, dichloromethane and thionyl chloride solution are added into reactor, and at 40 DEG C to be stirred at reflux 12 small
When, be concentrated under reduced pressure recovery dichloromethane and thionyl chloride, and Liquid Residue adds tetrahydrofuran, can be directly used for reacting and nothing in next step
It need to be further purified.
(4) IB-D preparation
Synthesis flow is as follows：
Preparation process：At 1 DEG C, to malononitrile under add diisopropylethylamine in dry tetrahydrofuran solution, charging terminates
Afterwards, it is warming up to and 1.5h is stirred at room temperature, be then cooled to 1 DEG C, IB-C dry tetrahydrofuran is slowly added into reaction mixture
Solution, after charging terminates, reaction mixture stirs 1.5 hours at 1 DEG C, is slowly added into water quenching and goes out reaction, after end is quenched, addition
15% aqueous ammonium chloride solution, is extracted with ethyl acetate, and organic extracts washed with water and the washing of 20% salt, concentration organic solvent obtain
Red oil crude product, recrystallized with Isosorbide-5-Nitrae-dioxane, centrifugation, be dried to obtain solid product IB-D.
(5) IB-E preparation
Synthesis flow is as follows：
Preparation process：Add IB-D into reactor, dioxane, potassium carbonate and dimethyl suflfate, after charging terminates, react
Mixed liquor is heated to 80 DEG C, stirs 3 hours, and be concentrated under reduced pressure recovery dioxane, adds water, is extracted with ethyl acetate, You Jicui
Liquid is taken to be washed with water, be concentrated under reduced pressure recovery ethyl acetate, crude product is obtained, with 1：1 normal heptane/re-crystallizing in ethyl acetate, from
The heart, drying obtain pale yellow solid product IB-E.
(6) IB-F preparation
Synthesis flow is as follows：
Preparation process：IB-E is added to reactor, 85% hydrazine hydrate is added in ethanol solution, after charging terminates, reaction is mixed
In 90 DEG C of backflow 2h, be concentrated under reduced pressure compound recovery ethanol, adds water crystallization, centrifugation, is dried to obtain solid IB-F.
(7) IB-G preparation
Synthesis flow is as follows：
Preparation process：IB-F is added in reactor, adds formamide, under nitrogen protection, is heated to 180 DEG C, and
4h is stirred at 180 DEG C, reactant mixture is cooled to 30 DEG C, water is added and centrifuges to obtain solid, and is washed with methanol, dry
To IB-G.
(8) prepared by IB-H
Synthesis flow is as follows：
Preparation process：By IB-G, triphenylphosphine and tetrahydrofuran are added in reactor, and (S)-N-BOC-3- is added after stirring
Hydroxy piperidine, diisopropyl azodiformate is subsequently added into, 8h, filtering reaction mixing is stirred at room temperature in reactant mixture
Thing, resulting solution add 20% brine It 2 times, organic phase concentration, are crystallized with methyl tertiary butyl ether(MTBE), filter, be dried to obtain
IB-H。
(9) IB-J preparation
Synthesis flow is as follows：
Preparation process：IB-H is added in reactor, dioxane is added, is passed through hydrogen chloride gas at 1 DEG C, is warming up to 25
DEG C stirring 1.5h, reaction solution concentration, residue add dichloromethane dissolving, add triethylamine, then be added dropwise plus acrylic acyl chlorides,
Stopping reaction after 2.5 hours, reactant mixture is washed with 5% lemon rubber aqueous acid, is then concentrated with salt water washing, organic layer,
Methylate tertbutyl ether crystallizes, filtering, obtained crude product, is heated to 40 DEG C of dissolvings after adding ethanol, adds activated carbon, continue
45 DEG C of stirring 2.5h, by diatomaceous filter cake heat filtering, gained filtrate is cooled to 1 DEG C of crystallization, and filtration drying obtains IB-J.
Embodiment 3
A kind of preparation method of Ibrutinib, comprises the following steps：
(1) IB-A preparation
Synthesis flow is as follows：
Preparation process：Under stirring at normal temperature, carbonic acid is added into IB-SM1 and IB-SM2 DMF solution
Potassium, cuprous iodide, after charging terminates, reaction mixture stirs 9 hours at 120 DEG C, and be concentrated under reduced pressure recovery N, N- dimethyl formyls
Amine, 900L water is added, is extracted with methyl tertiary butyl ether(MTBE), organic extract liquid washing, ethanol, gained are added after reclaiming organic solvent
IB-A ethanol solutions are directly used in react in next step.
(2) IB-B preparation
Synthesis flow is as follows：
Preparation process：Under stirring at normal temperature, the aqueous solution of sodium hydroxide is added into IB-A ethanol solutions, after charging terminates,
Reaction mixture stirs 2 hours at 80 DEG C, concentration and recovery ethanol, is cooled to 5 DEG C, in 5 DEG C plus 37% salt acid for adjusting pH value to 3,
Mixed liquor is stirred at room temperature 3 hours, by the centrifugation of caused solid, dries, obtains white solid product IB-B.
(3) IB-C preparation
Synthesis flow is as follows：
Preparation process：IB-B, dichloromethane and thionyl chloride solution are added into reactor, and at 50 DEG C to be stirred at reflux 13 small
When, be concentrated under reduced pressure recovery dichloromethane and thionyl chloride, and Liquid Residue adds tetrahydrofuran, can be directly used for reacting and nothing in next step
It need to be further purified.
(4) IB-D preparation
Synthesis flow is as follows：
Preparation process：At 2 DEG C, to malononitrile under add diisopropylethylamine in dry tetrahydrofuran solution, charging terminates
Afterwards, it is warming up to and 1.5h is stirred at room temperature, be then cooled to 2 DEG C, IB-C dry tetrahydrofuran is slowly added into reaction mixture
Solution, after charging terminates, reaction mixture stirs 1.5 hours at 2 DEG C, is slowly added into water quenching and goes out reaction, after end is quenched, addition
16% aqueous ammonium chloride solution, is extracted with ethyl acetate, and organic extracts washed with water and the washing of 25% salt, concentration organic solvent obtain
Red oil crude product, recrystallized with Isosorbide-5-Nitrae-dioxane, centrifugation, be dried to obtain solid product IB-D.
(5) IB-E preparation
Synthesis flow is as follows：
Preparation process：Add IB-D into reactor, dioxane, potassium carbonate and dimethyl suflfate, after charging terminates, react
Mixed liquor is heated to 90 DEG C, stirs 4 hours, and be concentrated under reduced pressure recovery dioxane, adds water, is extracted with ethyl acetate, You Jicui
Liquid is taken to be washed with water, be concentrated under reduced pressure recovery ethyl acetate, crude product is obtained, with 1：1 normal heptane/re-crystallizing in ethyl acetate, from
The heart, drying obtain pale yellow solid product IB-E.
(6) IB-F preparation
Synthesis flow is as follows：
Preparation process：IB-E is added to reactor, 80% hydrazine hydrate is added in ethanol solution, after charging terminates, reaction is mixed
In 100 DEG C of backflow 3h, be concentrated under reduced pressure compound recovery ethanol, adds water crystallization, centrifugation, is dried to obtain solid IB-F.
(7) IB-G preparation
Synthesis flow is as follows：
Preparation process：IB-F is added in reactor, adds formamide, under nitrogen protection, is heated to 190 DEG C, and
5h is stirred at 190 DEG C, reactant mixture is cooled to 40 DEG C, water is added and centrifuges to obtain solid, and is washed with methanol, dry
To IB-G.
(8) prepared by IB-H
Synthesis flow is as follows：
Preparation process：By IB-G, triphenylphosphine and tetrahydrofuran are added in reactor, and (S)-N-BOC-3- is added after stirring
Hydroxy piperidine, diisopropyl azodiformate is subsequently added into, 9h, filtering reaction mixing is stirred at room temperature in reactant mixture
Thing, resulting solution add 25% brine It 2 times, organic phase concentration, are crystallized with methyl tertiary butyl ether(MTBE), filter, be dried to obtain
IB-H。
(9) IB-J preparation
Synthesis flow is as follows：
Preparation process：IB-H is added in reactor, dioxane is added, is passed through hydrogen chloride gas at 2 DEG C, is warming up to 30
DEG C stirring 2h, reaction solution concentration, residue add dichloromethane dissolving, add triethylamine, then be added dropwise plus acrylic acyl chlorides, 3
Stop reaction after hour, reactant mixture is washed with 6% lemon rubber aqueous acid, then with salt water washing, organic layer concentration, adds first
Base tertbutyl ether crystallizes, filtering, obtained crude product, is heated to 45 DEG C of dissolvings after adding ethanol, adds activated carbon, continue at 50 DEG C
3h is stirred, by diatomaceous filter cake heat filtering, gained filtrate is cooled to 2 DEG C of crystallizations, and filtration drying obtains IB-J.
The better embodiment of the present invention is explained in detail above, but the present invention is not limited to above-mentioned embodiment party
Formula, can also be on the premise of present inventive concept not be departed from one skilled in the relevant art's possessed knowledge
Various changes can be made.
Claims (10)
1. a kind of preparation method of Ibrutinib, it is characterised in that comprise the following steps：
(1) IB-A preparation
(2) IB-B preparation
(3) IB-C preparation
(4) IB-D preparation
(5) IB-E preparation
(6) IB-F preparation
(7) IB-G preparation
(8) prepared by IB-H
(9) IB-J preparation
A kind of 2. preparation method of Ibrutinib according to claim 2, it is characterised in that the specific system in step (1)
Preparation Method is：Under stirring at normal temperature, potassium carbonate, iodate Asia are added into IB-SM1 and IB-SM2 DMF solution
Copper, after charging terminates, reaction mixture stirs 7-9 hours at 100-120 DEG C, and be concentrated under reduced pressure recovery DMF,
800-900L water is added, is extracted with methyl tertiary butyl ether(MTBE), organic extract liquid washing, ethanol, gained are added after reclaiming organic solvent
IB-A ethanol solutions are directly used in react in next step.
A kind of 3. preparation method of Ibrutinib according to claim 2, it is characterised in that the specific system in step (2)
Preparation Method is：Under stirring at normal temperature, the aqueous solution of sodium hydroxide is added into IB-A ethanol solutions, after charging terminates, reaction mixing
Liquid stirs 1-2 hours at 60-80 DEG C, concentration and recovery ethanol, is cooled to less than 10 DEG C, and below 10 DEG C plus 35-37% hydrochloric acid is adjusted
PH value is saved to 2-3,2-3 hours are stirred at room temperature in mixed liquor, by the centrifugation of caused solid, dry, obtain white solid product
IB-B。
A kind of 4. preparation method of Ibrutinib according to claim 2, it is characterised in that the specific system in step (3)
Preparation Method is：IB-B is added into reactor, dichloromethane and thionyl chloride solution are stirred at reflux 11-13 hours at 30-50 DEG C,
Be concentrated under reduced pressure recovery dichloromethane and thionyl chloride, and Liquid Residue adds tetrahydrofuran, can be directly used for reaction in next step without
It is further purified.
A kind of 5. preparation method of Ibrutinib according to claim 2, it is characterised in that the specific system in step (4)
Preparation Method is：0-2 DEG C, to malononitrile under diisopropylethylamine is added in dry tetrahydrofuran solution, after charging terminates, be warming up to
1-2h is stirred at room temperature, is then cooled to 0-2 DEG C, IB-C dry tetrahydrofuran solution is slowly added into reaction mixture, is added
After material terminates, reaction mixture stirs 1-2 hours at 0-2 DEG C, is slowly added into water quenching and goes out reaction, after end is quenched, addition 14-
16% aqueous ammonium chloride solution, is extracted with ethyl acetate, and organic extracts washed with water and the washing of 15-25% salt, concentrates organic solvent
Red oil crude product is obtained, is recrystallized with Isosorbide-5-Nitrae-dioxane, centrifugation, is dried to obtain solid product IB-D.
A kind of 6. preparation method of Ibrutinib according to claim 2, it is characterised in that the specific system in step (5)
Preparation Method is：Add IB-D into reactor, dioxane, potassium carbonate and dimethyl suflfate, after charging terminates, reaction mixture adds
Heat stirs 2-4 hours to 70-90 DEG C, and be concentrated under reduced pressure recovery dioxane, adds water, is extracted with ethyl acetate, organic extract liquid
It is washed with water, be concentrated under reduced pressure recovery ethyl acetate, crude product is obtained, with 1：1 normal heptane/re-crystallizing in ethyl acetate, centrifuge, dry
It is dry to obtain pale yellow solid product IB-E.
A kind of 7. preparation method of Ibrutinib according to claim 2, it is characterised in that the specific system in step (6)
Preparation Method is：Add IB-E to reactor, 80-90% hydrazine hydrates added in ethanol solution, after charging terminates, reactant mixture in
80-100 DEG C of backflow 1-3h, be concentrated under reduced pressure recovery ethanol, adds water crystallization, centrifugation, is dried to obtain solid IB-F.
A kind of 8. preparation method of Ibrutinib according to claim 2, it is characterised in that the specific system in step (7)
Preparation Method is：IB-F is added in reactor, adds formamide, under nitrogen protection, is heated to 170-190 DEG C, and
3-5h is stirred at 170-190 DEG C, reactant mixture is cooled to 20-40 DEG C, water is added and centrifuges to obtain solid, and washed with methanol
Wash, be dried to obtain IB-G.
A kind of 9. preparation method of Ibrutinib according to claim 1, it is characterised in that the specific system in step (8)
Preparation Method is：By IB-G, triphenylphosphine and tetrahydrofuran are added in reactor, and (S)-N-BOC-3- hydroxyl piperazines are added after stirring
Pyridine, diisopropyl azodiformate is subsequently added into, 7-9h is stirred at room temperature in reactant mixture, filters reactant mixture, institute
Obtain solution and add 15-25% brine Its 2 times, organic phase concentration, crystallized with methyl tertiary butyl ether(MTBE), filter, be dried to obtain IB-
H。
A kind of 10. preparation method of Ibrutinib according to claim 1, it is characterised in that the specific system in step (9)
Preparation Method is：IB-H is added in reactor, dioxane is added, is passed through hydrogen chloride gas at 0-2 DEG C, is warming up to 20-30 DEG C
1-2h is stirred, reaction solution concentrates, and residue adds dichloromethane dissolving, adds triethylamine, is then added dropwise and adds acrylic acyl chlorides, 2-
Stopping reaction after 3 hours, reactant mixture is washed with 4-6% lemon rubber aqueous acids, is then concentrated with salt water washing, organic layer,
Methylate tertbutyl ether crystallizes, filtering, obtained crude product, is heated to 35-45 DEG C of dissolving after adding ethanol, adds activated carbon,
40-50 DEG C of stirring 2-3h, by diatomaceous filter cake heat filtering, gained filtrate is cooled to 0-2 DEG C of crystallization, and filtration drying obtains
IB-J。
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113004203A (en) * | 2021-03-05 | 2021-06-22 | 江苏慧聚药业有限公司 | Relevant substance of ibrutinib core fragment and synthetic method thereof |
| CN113200987A (en) * | 2021-04-29 | 2021-08-03 | 湖南华腾制药有限公司 | Preparation method of ibrutinib |
| WO2022056100A1 (en) * | 2020-09-10 | 2022-03-17 | Loxo Oncology, Inc. | Processes and intermediates for the preparation of (s)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane-2-yl)-1h-pyrazole-4-carboxamide |
| CN114853764A (en) * | 2022-04-21 | 2022-08-05 | 埃斯特维华义制药有限公司 | Preparation process of ibrutinib |
| CN114853764B (en) * | 2022-04-21 | 2024-04-26 | 埃斯特维华义制药有限公司 | Preparation process of ibutenib |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2022056100A1 (en) * | 2020-09-10 | 2022-03-17 | Loxo Oncology, Inc. | Processes and intermediates for the preparation of (s)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane-2-yl)-1h-pyrazole-4-carboxamide |
| CN113004203A (en) * | 2021-03-05 | 2021-06-22 | 江苏慧聚药业有限公司 | Relevant substance of ibrutinib core fragment and synthetic method thereof |
| CN113004203B (en) * | 2021-03-05 | 2022-04-19 | 江苏慧聚药业股份有限公司 | Relevant substance of ibrutinib core fragment and synthetic method thereof |
| CN113200987A (en) * | 2021-04-29 | 2021-08-03 | 湖南华腾制药有限公司 | Preparation method of ibrutinib |
| CN114853764A (en) * | 2022-04-21 | 2022-08-05 | 埃斯特维华义制药有限公司 | Preparation process of ibrutinib |
| CN114853764B (en) * | 2022-04-21 | 2024-04-26 | 埃斯特维华义制药有限公司 | Preparation process of ibutenib |
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