CN106188062A - Replace the preparation method of Buddhist nun according to Shandong, replace intermediate and the preparation method of intermediate of Buddhist nun according to Shandong - Google Patents
Replace the preparation method of Buddhist nun according to Shandong, replace intermediate and the preparation method of intermediate of Buddhist nun according to Shandong Download PDFInfo
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- CN106188062A CN106188062A CN201510232623.6A CN201510232623A CN106188062A CN 106188062 A CN106188062 A CN 106188062A CN 201510232623 A CN201510232623 A CN 201510232623A CN 106188062 A CN106188062 A CN 106188062A
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Abstract
The invention provides a kind of according to Shandong for the preparation method of Buddhist nun, react with dithyl sulfate including (a) compound (3) and obtain compound (4)；B () compound (4) and hydrazine dihydrochloride react and obtain compound (5)；C () compound (5) and Methanamide react and obtain compound (6)；D () compound (6) and (R)-1-Boc-3-hydroxy piperidine react after terminating, add acid and make compound (7) occur deprotection reaction to obtain compound (8)；And (e) compound (8) reacts with acryloyl chloride and obtains compound (9) according to Shandong for Buddhist nun.Present invention also offers a kind of formula (4) according to Shandong for Buddhist nun's intermediate and the preparation method of midbody compound (8).The method low cost of the present invention, safety is good and yield high, is suitable for large-scale production.Reaction scheme is as follows.
Description
Technical field
The present invention relates to small-molecule drug field, relate more specifically to a kind of preparation method replacing Buddhist nun according to Shandong, according to Shandong
Intermediate and the preparation method of this intermediate for Buddhist nun.
Background technology
Cancer is a kind of major disease of current facing mankind, has substantial amounts of patient every year because suffering from cancer
Pass away.Buddhist nun (Ibrutinib) is replaced to be that a kind of oral entitled bruton's tyrosine kinase (BTK) presses down according to Shandong
The heavyweight PTS of preparation.This medicine by with target protein BTK active site cysteine residue
(Cys-481) optionally covalent bond, irreversibility ground suppression BTK, thus effectively stop tumor
Move to be adapted to the lymphoid tissue of tumor growth environment from B cell.This medicine drenches except treatment jacket cell
Outside bar tumor, it is additionally operable to treat chronic lymphocytic leukemia, small lymphocyte lymphoma.
Patent US 20080108636 reports the synthesis of Ibrutinib.The synthetic route used in this patent
Following reaction scheme 1, its reaction is with 4-phenoxy benzoic acid as substrate, through acylation reaction, condensation, first
Base, cyclization, Mitsunobu reaction and allyl acylation reaction obtain final products.Its preparation process
Need to use trimethyl silicane base Azimethylene., there is potential safety hazard.It addition, Mitsunobu reaction employs
The triphenylphosphine of load, expensive.It needs temperature to be up to 180 DEG C the highest with formamide,
It is unfavorable for commercial production.
Reaction scheme 1
Chinese patent CN 10362677 and world patent WO 201482598, WO 201468527 report
The method of preparing Ibrutinib as methylating reagent by dimethyl sulfate, wherein methylation reaction compares
Difficulty, and yield is the highest.The more important thing is that dimethyl sulfate belongs to toxic articles, used by restriction, put for it
Big production brings difficulty.
It addition, patent WO2013003629 and CN 03121999 report the most different a kind of synthesis
Route.
In the method, the coupling reaction of intermediate preparation process uses heavy metal Pd catalyst, brings a huge sum of money
Belong to the hidden danger of residual, cause with high costs, reduce the market competitiveness, be unfavorable for amplifying production.
Summary of the invention
In order to overcome the problems referred to above of the prior art, the invention provides a kind of preparation side replacing Buddhist nun according to Shandong
Method, replaces intermediate and the preparation method of intermediate of Buddhist nun according to Shandong, and the method cost of the present invention is lower, safety
Good and reaction yield is greatly improved, and is suitable for large-scale production.
The technical solution used in the present invention is:
On the one hand, the invention provides a kind of preparation method replacing Buddhist nun according to Shandong, comprise the following steps:
With dithyl sulfate in organic solvent, at 50～100 DEG C, there is enol ether in (a) compound (3)
Reaction, obtains compound (4), preferably 60～80 DEG C；
The compound (4) obtained in (b) step (a) and hydrazine dihydrochloride in organic solvent, 35～100
There is cyclization at DEG C, obtain compound (5), preferably 65～95 DEG C；
The compound (5) obtained in (c) step (b) and Methanamide in organic solvent, at the bar that acid exists
React at 90～150 DEG C under part, obtain compound (6), preferably 110～130 DEG C；
The compound (6) obtained in (d) step (c) and (R)-1-Boc-3-hydroxy piperidine in organic solvent,
Reacting under conditions of triphenylphosphine exists, reaction obtains the solution of compound (7) after terminating, then to
Adding acid in this solution makes compound (7) occur deprotection reaction to obtain compound (8)；And
The compound (8) obtained in (e) step (d) and acryloyl chloride in organic solvent ,-25～30
React at DEG C, obtain compound (9) according to Shandong for Buddhist nun, preferably-10～20 DEG C；
Reaction scheme is as follows:
Further, in step (a), enol etherification reaction is carried out in the presence of a base.
Preferably, the alkali in above-mentioned steps (a) selected from sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate,
In sodium hydroxide, potassium hydroxide, triethylamine, diisopropyl ethyl ammonia, DMAP, pyridine
One or more.
It is highly preferred that in step (a), organic solvent selected from Isosorbide-5-Nitrae-dioxane, dichloromethane, four
One or more in hydrogen furan, toluene, benzene, 2-methyltetrahydrofuran.
Further, in step (b), reaction is carried out in the presence of a base.
Preferably, the alkali in above-mentioned steps (b) selected from triethylamine, sodium bicarbonate, sodium carbonate, potassium carbonate,
In potassium bicarbonate, sodium hydroxide, potassium hydroxide, diisopropyl ethyl ammonia, DMAP, pyridine
One or more.
It is highly preferred that in step (b), organic solvent is selected from ethanol, methanol, methyl tertiary butyl ether(MTBE), first
One or more in benzene, dichloromethane, chloroform.
Further, in step (c), one or more in acetic acid, butanoic acid, benzoic acid of acid.
Preferably, in step (c), organic solvent is selected from Methanamide.
Further, in step (d), two-step reaction the most at room temperature reacts, preferably 20～50 DEG C.
Preferably, in step (d), acid is selected from concentrated hydrochloric acid or other forms of hydrochloric acid.
Preferably, in step (d), organic solvent is selected from Isosorbide-5-Nitrae-dioxane, oxolane, methyl
One or more in oxolane, dichloromethane, benzene, toluene.
It is highly preferred that in step (e), organic solvent selected from dichloromethane, chloroform, oxolane,
In N,N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, methyltetrahydrofuran, toluene one
Plant or several.
On the other hand, present invention also offers one such as following formula (I) replaces Buddhist nun's intermediate according to Shandong,
Wherein, R represents C2～C6Alkyl.
Preferably, R represents ethyl, and the most preferred above-mentioned intermediate has such as the concrete structure of following formula (4):
It yet still another aspect, present invention also offers the preparation side replacing Buddhist nun's intermediate according to Shandong of a kind of above-mentioned formula (I)
Method, obtains the step of compound (I), reaction scheme including formula (3) compound generation enol etherification reaction
As follows:
Wherein: R represents C2～C6Alkyl.
Preferably, formula (3) compound and dithyl sulfate generation enol etherification reaction obtain compound (I),
Wherein R represents ethyl.
According to a further aspect in the invention, it is provided that a kind of such as the preparation replacing Buddhist nun's intermediate according to Shandong of following formula (8)
Method, comprises the following steps: compound (6) and (R)-1-Boc-3-hydroxy piperidine in organic solvent,
Triphenylphosphine reacts under conditions of existing, and reaction obtains the solution of compound (7) after terminating, then to this
Adding acid in solution makes compound (7) occur deprotection reaction to obtain compound (8), and reaction scheme is as follows:
Preferably, two-step reaction is the most at room temperature carried out, preferably 20～50 DEG C.
It is highly preferred that other forms that acid is concentrated hydrochloric acid or hydrochloric acid.
It is highly preferred that organic solvent is selected from Isosorbide-5-Nitrae-dioxane, toluene, oxolane, dichloromethane, chlorine
One or more in Fang.
According to another aspect of the invention, present invention also offers the preparation method of a kind of compound (3), bag
Include following steps: compound (1) with thionyl chloride in organic solvent, obtains at 80 DEG C～110 DEG C of reactions
Compound (2)；Compound (2) and Cyanoacetyl-Cyacetazid in organic solvent, in the presence of a base at 0 DEG C～60
The reaction that DEG C reacts obtains compound (3), and reaction scheme is as follows:
Wherein, the solvent used in the above steps of the present invention can use other with identical functions
Solvent replaces, and is not limited to described solvent, and those skilled in the art can use by selectivity according to actual needs.
Raw material and reagent that in the present invention, each step is used all can be bought by commercial sources, it is possible to according to often
Rule chemical means synthesis, such as compound (3) can directly be bought, it is possible to is synthesized by said method.
Compared with prior art, the invention have the advantages that the invention provides a kind of according to Shandong for the system of Buddhist nun
Preparation Method, the method is avoided using expensive metal catalysis, thus is reduced production cost；The present invention is with sulphuric acid
Diethylester substitutes methylating reagent, and cheap, easy to operate, safety is good；Additionally, the side of the present invention
It is isolated and purified easily that method is not related to environmentally harmful solvent, intermediate and product, simple to operate, Er Qieben
Invention, by the adjustment to reaction condition, improves reaction yield, is suitable for large-scale production.The present invention provides
The another kind of new intermediate (I) replacing Buddhist nun according to Shandong, additionally provides a kind of system replacing Buddhist nun's intermediate (8) according to Shandong
Preparation Method, there is the reaction of prolonging of light in compound (6), intermediate product (7) is not required to separate, and one kettle way is direct
Prepare compound (8), it is provided that reaction yield.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is described in further detail, in order to those skilled in the art can
It is more fully understood that the present invention, thus protection scope of the present invention is made apparent clear and definite defining.
Embodiment 1
Synthesis compound (2)
Measure toluene (4Vol, relative to the volume multiple of compound 1 mass) and add in reactor, claim
Take 1eq compound (1) to add in aforesaid reaction vessel.Add thionyl chloride (1.5eq), heat 110 DEG C instead
Should convert completely to raw material, rotation is evaporated off solvent, obtains crude product, is directly used in next step reaction.
Embodiment 2
Synthesis compound (3)
Me-THF (1Vol) solution of preparation Cyanoacetyl-Cyacetazid (1.1eq), drops to NaH's (2eq)
In Me-THF (2Vol) solution, Cyanoacetyl-Cyacetazid drips complete follow-up continuous stirring 30min.By 1eq compound
(2) it is dissolved in Me-THF (2Vol) wiring solution-forming, drops in above-mentioned reactant liquor.It is added dropwise to complete continuation
Stirring terminates to reaction.1N hydrochloric acid is added to PH=2-3, addition water (4Vol) separatory to reactant liquor.Water
It is extracted twice with EA (3Vol) mutually, merges organic facies, be spin-dried for obtaining crude product.Crude product through recrystallization purifying,
Yield 95%.
The nuclear magnetic data of product is as follows:
1H NMR(400MHz,DMSO)δ7.67–7.59(m,2H),7.48–7.37(m,2H),
7.19 (t, J=7.4Hz, 1H), 7.09 7.02 (m, 2H), 6.99 6.91 (m, 2H).
Embodiment 3
Synthesis compound (4)
Weigh Compound 3 (1eq), adds Isosorbide-5-Nitrae-Dioxane (5vol), stirring and dissolving.Weigh NaHCO3
(1.5eq), join in reactor.System is heated to 70 DEG C, drips Et2SO4(2eq)。HPLC
Monitoring reaction completes, and cools.EA (4vol) extracts, and washes with saturated aqueous common salt (4vol).
It is dried, is spin-dried for, obtains crude product, be directly used in next step reaction.
Embodiment 4
Synthesis compound (5)
By above-mentioned gained compound 4 (1eq), add EtOH (5vol), stirring and dissolving.Add hydrazine two
Hydrochlorate (1eq), dropping triethylamine (3eq), feed complete, outer temperature arranges 85 DEG C, begins to warm up
To having reacted.Cooling, rotation is evaporated off major part ethanol.Gained crude product is added in a large amount of water, analysis
Go out product, yield > 95%.
The nuclear magnetic data of product is as follows:
1H NMR (400MHz, DMSO) δ 12.12 (s, 1H), 7.82 (d, J=8.2Hz, 2H), 7.42
(t, J=7.5Hz, 2H), 7.31 6.98 (m, 5H), 6.47 (s, 2H).
Embodiment 5
Synthesis compound (6)
Reactor adds Methanamide (5Vol), adds compound 5 (1eq) and stir.Add
Me2NCH(OMe)2(3.5eq) with AcOH (4eq).Outer temperature arranges 120 DEG C of reacting by heating.Reaction knot
Bundle natural cooling, is filtrated to get compound 6.The purified sterling that obtains of compound 6, HPLC > 99%, receives
Rate 52%
The nuclear magnetic data of product is as follows:
1H NMR (400MHz, DMSO) δ 13.57 (s, 1H), 8.23 (s, 1H), 7.68 (d, J=8.5
Hz, 2H), 7.44 (t, J=7.8Hz, 2H), 7.26 7.02 (m, 5H), 6.87 (d, J=55.5Hz,
1H)。
Embodiment 6
Synthesis compound (7)
In reaction bulb, add triphenylphosphine (2.5eq), add Isosorbide-5-Nitrae-dioxane (25Vol), stir molten
Solve.Addition compound (R)-1-Boc-3-hydroxy piperidine (1.5eq), compound 6 (1.0eq), anti-under room temperature
Should be complete to consumption of raw materials.It is directly used in next step reaction.
Embodiment 7
Synthesis compound (8)
At room temperature, in above-mentioned reactant liquor, concentrated hydrochloric acid (2.3Vol), compound (7) being converted into are added
Compound (8).Raw material converts completely, and rotation is evaporated off major part solvent.DCM (6Vol) is added in crude product
With water (6Vol), separatory.Organic phase washed with water (6Vol) extracts once.Merge aqueous phase, with DCM (6Vol)
Wash three times.Aqueous phase adjusts pH to 9-10, separates out a large amount of solid chemical compound 8, yield 81.1%.
The nuclear magnetic data of product is as follows:
1H NMR(400MHz,CDCl3) δ 8.35 (s, 1H), 8.01 (s, 1H), 7.65 (d, J=8.6Hz,
2H), 7.39 (t, J=8.0Hz, 2H), 7.20 7.13 (m, 3H), 7.08 (d, J=7.7Hz, 2H), 5.86
(s, 2H), 4.82 (tt, J=9.2,4.7Hz, 1H), 3.35 3.21 (m, 2H), 3.06 (d, J=12.9Hz,
1H),2.80–2.68(m,1H),2.39–2.05(m,4H),1.95–1.84(m,1H),1.74–1.59
(m,1H)。
Embodiment 8
Synthesis compound (9)
Compound (8) (1eq), DCM (27Vol) and potassium carbonate (1.5eq) is added in reaction bulb.
System is cooled to-2～10 DEG C, DCM (13Vol) solution of dropping acryloyl chloride (0.95eq).Instead
Should complete, add water (10Vol) separatory.Aqueous phase DCM extracts (10Vol) twice.Merge organic
Phase, washes three times with 1N HCl (10Vol), and saturated sodium bicarbonate (10Vol) is washed once, saturated common salt
Water (10Vol) is washed once.Anhydrous sodium sulfate is dried, and filters and is spin-dried for obtaining crude product.Crude product is purified obtains chemical combination
Thing 9, yield 90%.
The nuclear magnetic data of product is as follows:
1H NMR(400MHz,CDCl3) δ 8.34 (s, 1H), 7.65 (d, J=8.6Hz, 2H), 7.38
(dd, J=11.8,4.1Hz, 2H), 7.16 (t, J=8.8Hz, 3H), 7.11 7.01 (m, 2H),
6.70-6.47(m,1H),6.36-6.20(m,1H),6.00(br,2H),5.77-5.55(m,1H),
4.98-4.45(m,2H),4.33–3.90(m,1H),3.88-3.29(m,1H),3.28-2.71(m,1H),
2.50-2.14(m,3H),2.06–1.89(m,1H),1.83-1.60(m,1H)。
Above only certain embodiments of the present invention is illustrated, but the protection content of the present invention not only limits
In above example, in the art of the present invention, the usual knowledge of a GPRS, it is possible at it
Diversified change is carried out in the range of technology main idea.
Claims (10)
1. the preparation method replacing Buddhist nun according to Shandong, it is characterised in that comprise the following steps:
With dithyl sulfate in organic solvent, at 50～100 DEG C, there is enol ether in (a) compound (3)
Reaction, obtains compound (4)；
The compound (4) obtained in (b) step (a) and hydrazine dihydrochloride in organic solvent, 35～100
There is cyclization at DEG C, obtain compound (5)；
The compound (5) obtained in (c) step (b) and Methanamide in organic solvent, at the bar that acid exists
React at 90～150 DEG C under part, obtain compound (6)；
The compound (6) obtained in (d) step (c) and (R)-1-Boc-3-hydroxy piperidine in organic solvent,
Reacting under conditions of triphenylphosphine exists, reaction obtains the solution of compound (7) after terminating, then to
Adding acid in this solution makes compound (7) occur deprotection reaction to obtain compound (8)；And
The compound (8) obtained in (e) step (d) and acryloyl chloride in organic solvent ,-25～30
React at DEG C and obtain compound (9) according to Shandong for Buddhist nun；
Reaction scheme is as follows:
The preparation method replacing Buddhist nun according to Shandong the most according to claim 1, it is characterised in that: in step (a),
Described enol etherification reaction is carried out in the presence of a base, and described alkali is selected from sodium bicarbonate, sodium carbonate, carbon
Acid potassium, potassium bicarbonate, sodium hydroxide, potassium hydroxide, triethylamine, diisopropyl ethyl ammonia, 4-diformazan ammonia
One or more in yl pyridines, pyridine.
The preparation method replacing Buddhist nun according to Shandong the most according to claim 1, it is characterised in that: in step (b),
Described reaction is carried out in the presence of a base, and described alkali is selected from sodium bicarbonate, sodium carbonate, potassium carbonate, carbon
Potassium hydrogen phthalate, sodium hydroxide, potassium hydroxide, triethylamine, diisopropyl ethyl ammonia, DMAP,
One or more in pyridine.
The preparation method replacing Buddhist nun according to Shandong the most according to claim 1, it is characterised in that: in step (c),
Described acid is selected from acetic acid, butanoic acid or benzoic acid.
The preparation method replacing Buddhist nun according to Shandong the most according to claim 1, it is characterised in that: in step (d),
Described organic solvent selected from 1,4-dioxane, oxolane, methyltetrahydrofuran, dichloromethane, benzene,
One or more in toluene.
6. as following formula (I) according to Shandong for Buddhist nun's intermediate,
Wherein, R represents C2～C6Alkyl.
The most according to claim 6 according to Shandong for Buddhist nun's intermediate, it is characterised in that: R represents ethyl, described in
Mesosome has such as following formula (4) concrete structure:
8. the preparation method replacing Buddhist nun's intermediate according to Shandong described in a claim 6, it is characterised in that: include formula (3)
Compound generation enol etherification reaction obtains the step of compound (I), and reaction scheme is as follows:
Wherein: R represents C2～C6Alkyl.
The preparation method replacing Buddhist nun's intermediate according to Shandong the most according to claim 8, it is characterised in that: (3) chemical combination
Thing and dithyl sulfate generation enol etherification reaction obtain compound (I), and wherein R represents ethyl.
10. the preparation method replacing Buddhist nun's intermediate according to Shandong of a kind such as following formula (8), it is characterised in that include following step
Rapid: compound (6) and (R)-1-Boc-3-hydroxy piperidine in organic solvent, at the bar that triphenylphosphine exists
Reacting under part, reaction obtains the solution of compound (7) after terminating, then adds making of acid in this solution
Compound (7) occurs deprotection reaction to obtain compound (8), and reaction scheme is as follows:
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| CN107233344A (en) * | 2017-07-20 | 2017-10-10 | 河南师范大学 | A kind of antineoplastic replaces the preparation method of Buddhist nun according to Shandong |
| CN107383017A (en) * | 2017-07-20 | 2017-11-24 | 河南师范大学 | Buddhist nun's high efficiency preparation method is replaced according to Shandong |
| CN108349980A (en) * | 2015-10-28 | 2018-07-31 | 台湾神隆股份有限公司 | It is used to prepare according to Shandong for Buddhist nun and its method of intermediate |
| CN113200987A (en) * | 2021-04-29 | 2021-08-03 | 湖南华腾制药有限公司 | Preparation method of ibrutinib |
| CN113200986A (en) * | 2021-04-29 | 2021-08-03 | 湖南华腾制药有限公司 | Preparation method of ibrutinib intermediate |
| CN113214261A (en) * | 2020-01-21 | 2021-08-06 | 尚科生物医药（上海）有限公司 | Purification method of ibrutinib crystal form A |
| CN114853764A (en) * | 2022-04-21 | 2022-08-05 | 埃斯特维华义制药有限公司 | Preparation process of ibrutinib |
| CN115124536A (en) * | 2022-07-02 | 2022-09-30 | 浙江美诺华药物化学有限公司 | Synthesis method of ibrutinib intermediate |
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108349980A (en) * | 2015-10-28 | 2018-07-31 | 台湾神隆股份有限公司 | It is used to prepare according to Shandong for Buddhist nun and its method of intermediate |
| CN107233344A (en) * | 2017-07-20 | 2017-10-10 | 河南师范大学 | A kind of antineoplastic replaces the preparation method of Buddhist nun according to Shandong |
| CN107383017A (en) * | 2017-07-20 | 2017-11-24 | 河南师范大学 | Buddhist nun's high efficiency preparation method is replaced according to Shandong |
| CN107383017B (en) * | 2017-07-20 | 2020-01-14 | 河南师范大学 | Efficient preparation method of ibrutinib |
| CN113214261A (en) * | 2020-01-21 | 2021-08-06 | 尚科生物医药（上海）有限公司 | Purification method of ibrutinib crystal form A |
| CN113200987A (en) * | 2021-04-29 | 2021-08-03 | 湖南华腾制药有限公司 | Preparation method of ibrutinib |
| CN113200986A (en) * | 2021-04-29 | 2021-08-03 | 湖南华腾制药有限公司 | Preparation method of ibrutinib intermediate |
| 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 |
| CN115124536A (en) * | 2022-07-02 | 2022-09-30 | 浙江美诺华药物化学有限公司 | Synthesis method of ibrutinib intermediate |
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Application publication date: 20161207 |