CN103121999A - Method for synthesizing tyrosine kinase inhibitor PCI-32765 - Google Patents
Method for synthesizing tyrosine kinase inhibitor PCI-32765 Download PDFInfo
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- CN103121999A CN103121999A CN2012103103439A CN201210310343A CN103121999A CN 103121999 A CN103121999 A CN 103121999A CN 2012103103439 A CN2012103103439 A CN 2012103103439A CN 201210310343 A CN201210310343 A CN 201210310343A CN 103121999 A CN103121999 A CN 103121999A
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- pyrazolo
- pyrimidine
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a method for synthesizing tyrosine kinase inhibitor PCI-32765. The method comprises the following steps of: 1) carrying out a coupled reaction between a compound 10 and a compound 15 to obtain a compound 6; 2) reacting the compound 6 with a compound 16 to obtain a compound 11 in the presence of a more ideal catalyst; 3) protecting the compound 11 to obtain a compound 12; 4) carrying out selective de-protection on the compound 12 to obtain a compound 13; 5) attacking the compound 13 which has only one position which can be attacked by a compound 17 to obtain a very pure compound 14; and 6) removing protecting groups, thus obtaining the PCI-32765. By the method, tyrosine kinase which serves as a main receptor signal of B cells can be inhibited, and the tyrosine kinase inhibitor PCI-32765 is not only capable of inhabiting the generation of hemocyte with little toxicity and side effects, but also is moderate in reaction conditions, simple to operate, convenient to purify, low in cost, environment-friendly, and suitable for large scale production.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, particularly relate to the synthetic method of a kind of tyrosine kinase inhibitor PCI-32765.
Background technology
PCI-32765(Ibrutinib), chemical name: 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-yl]-piperidino]-2-propylene-1-ketone, its structural formula is as follows:
PCI-32765 is a kind of oral medicine, and it can suppress the Tyrosylprotein kinase as B cell principal recipient signal, promotes the program necrocytosis, stops cell migration, and is attached on malignant B cell.
Basic patent US20080108636 discloses a synthetic route:
This synthetic route obtains the finished product take the 4-phenoxy benzoic acid as raw material through the reaction of eight steps, and reactions steps is as follows:
There is following shortcoming in above-mentioned the method:
ⅰ, the single line reaction of eight steps, route is long, and economy is bad;
Will use trimethyl silicane diazomethane (TMSCHN2) when ⅱ, synthetic intermediate 4, this material is easily fried, and danger coefficient is larger, and the possibility of its large-scale production is reduced greatly;
When ⅲ, synthetic intermediate 7, use the triphenyl phosphorus of polymer-bound, raw material is commonly used in deindustrialization, and is expensive, and cost is high;
When ⅳ, final step acidylate, poor selectivity produces a large amount of negative products, purifies very difficult, and reaction is difficult to amplify.
In a word, this route raw material is uncommon, price, and step is long, and cost is high, and reaction is dangerous, and side reaction is many, and purification difficult has limited the possibility of this route suitability for industrialized production.
Summary of the invention
The technical problem that the present invention mainly solves is to provide the synthetic method of a kind of tyrosine kinase inhibitor PCI-32765; can suppress the Tyrosylprotein kinase as B cell principal recipient signal; generation and the toxic side effect that can not only suppress hemocyte are less; and reaction conditions is gentle; simple to operate, be convenient to purifying, with low cost; environmental friendliness is fit to large-scale production.
For solving the problems of the technologies described above, the technical scheme that the present invention adopts is: the synthetic method of a kind of tyrosine kinase inhibitor PCI-32765 is provided, and its reactions steps is as follows:
The invention has the beneficial effects as follows: the synthetic method of a kind of tyrosine kinase inhibitor PCI-32765 of the present invention; can suppress the Tyrosylprotein kinase as B cell principal recipient signal; generation and the toxic side effect that can not only suppress hemocyte are less; and reaction conditions is gentle; simple to operate, be convenient to purifying, with low cost; environmental friendliness is fit to large-scale production.
Embodiment
The below is described in detail preferred embodiment of the present invention, thereby so that advantages and features of the invention can be easier to be it will be appreciated by those skilled in the art that, protection scope of the present invention is made more explicit defining.
The embodiment of the present invention comprises:
The synthetic method of a kind of tyrosine kinase inhibitor PCI-32765 is drawn together following steps:
1, compound 10 obtains compound 6 with compound 15 generation linked reactions;
2, compound 6 obtains in the process of compound 11 with compound 16 reactions, and we have selected more preferably catalyzer;
3, compound 11 obtains compound 12 by protection;
4, compound 12 selectivity deprotections obtain compound 13;
5, compound 13 only is left unique position for compound 17 attacks, obtains very pure compound 14;
6, take off protecting group and obtain PCI-32765
Wherein compound 10,15, and 16,17 can utilize the compound of reagent agent or technical grade, perhaps utilize relevant method and technology to synthesize.
In the present invention in step 1), alkaline reagents deposit with the catalyzer existence condition under, in suitable solvent, the Suzuki linked reactions occur with compound 15 and generate compounds 6 in compound 10.Alkaline reagents can be selected cesium carbonate, salt of wormwood, sodium carbonate, sodium bicarbonate, sodium phosphate, potassiumphosphate, potassiumphosphate, sodium-acetate, Potassium ethanoate, and wherein the activity with Potassium ethanoate is the strongest.Catalyzer can use PdCl2 (PPh3) 2, PdCl2-Mn (OAc) 2, Pd (TMHD) 2, PdCl2 (PhCN) 2, Pd (dppf) 2Cl2, has best catalytic effect.Solvent can be selected aprotic solvent, comprises ethers, as THF, and Isosorbide-5-Nitrae-dioxane etc.; Polar aprotic solvent is as DMSO, DMF, NMP etc.The preferred 40-90 of temperature of reaction ℃, under different reaction conditionss, the control that is beneficial to react in this temperature range and the purifying of product are principle, select different temperature of reaction.
This reactions steps 2) in, can react smoothly under the mineral alkali catalytic condition, and patent US20080108636 needs the catalyst system of polymer-bound palladium.Mineral alkali can be selected cesium carbonate, salt of wormwood, sodium carbonate, sodium bicarbonate, sodium phosphate, potassiumphosphate, and potassiumphosphate, sodium-acetate, Potassium ethanoate are wherein best with the effect of cesium carbonate.The solvent system selection ethers is such as ether, isopropyl ether, methyl tertiary butyl ether, THF etc.Temperature range is 30-80 ℃.
In step 3) of the present invention, first amino is protected, made subsequent reactions have specificity, prevent the generation of by product.Make acid binding agent with organic bases triethylamine, diisopropylethylamine, pyridine, two cyclohexyl amines.Solvent can be ethers and halogenated hydrocarbon, can complete this reaction under room temperature.
By protecting amino, later step 4 of the present invention), 5), 6) just can obtain very much highly purified target product through easily by common method.
Embodiment 1
The preparation of compound 6
Under nitrogen protection; the compound 10 of 0.1moL and 1.5 equivalent compounds 15 and 800mL dioxane are joined in the 2L reaction flask; add again sodium-acetate 1.5 equivalents and catalyst P dCl2 (PPh3) 2 0.2 equivalents; 50-60 ℃ was reacted 5 hours, filtered while hot, filter residue washing with alcohol three times; merging filtrate; concentrate and obtain solid, obtain pure product 16.2 grams, yield 60% with the ethanol rinsing
Embodiment 2
The preparation of compound 6
Under nitrogen protection; the compound 10 of 0.1moL and 1.5 equivalent compounds 15 and 800mL DMF are joined in the 2L reaction flask; add again sodium-acetate 1.5 equivalents and catalyst P dCl2 (PhCN) 2 0.2 equivalents; 50-60 ℃ was reacted 5 hours, filtered while hot, filter residue washing with alcohol three times; merging filtrate; concentrate and obtain solid, namely get pure product 21.5 grams, yield 71% with the ethanol rinsing.
Embodiment 3
The preparation of compound 11
The compound 6 of 0.1moL and 1.2 equivalent compounds 16 and 1000mL THF are joined in the 2L reaction flask, add again 1.5 equivalent cesium carbonates, refluxed 24 hours, after reaction finishes, concentrated most of solvent, with remaining pouring in large water gaging, separate out solid, filter, wash to such an extent that compound 36.9 digests compound 11, yield 76% need not to be further purified.
Embodiment 4
The preparation of compound 12
Just the compound 11 of 0.1moL and 1.2 equivalent compound trifluoroacetyl chlorides and 1000mL THF join in the 2L reaction flask, add 2.5 triethylamines, 30-40 ℃ was reacted 24 hours, after reaction finishes again, concentrated solvent, thin up, then use ethyl acetate extraction, washing, saturated sodium-chloride respectively once, reconcentration ethyl ester ethyl ester gets product 50.1 grams, and yield 86% is directly used in next step reaction.
Embodiment 5
The preparation of compound 13
With in the compound 12 of 0.1moL and 500mL methyl alcohol and the hydrochloric acid of 50mL 6N join in the reaction flask of 1L, stirring at room 3 hours, reaction is completed very soon, and have solid to separate out, and filtering, solid is with the ethyl acetate washing for several times, get the pure compound 13 of 38.5 grams, yield 80%.
Embodiment 6
The preparation of compound 14
The compound 13 of 0.1moL and 1.2 equivalent acrylate chlorides and 1L methylene dichloride are joined in the 2L reaction flask, and 20-40 ℃ of triethylamine that drips 1.2 equivalents finishes rear stirring at room 3 hours, react the complete rear dichloromethane extraction of using, concentrated, obtain product 47.7 grams, yield 89%.Need not to be further purified.
Embodiment 7
The preparation of PCI-32765
With 0.1moL compound 14 and 800mL methyl alcohol and the little solution of 160mL saturated sodium carbonate, 50-60 ℃ was reacted 5 hours, dilute with water after reaction is completed, concentrated, then use dichloromethane extraction, get crude product after concentrating, use the toluene recrystallization, obtain the finished product 28.6 grams, yield 65%.HPLC purity 98.6%, e.e.%〉98%.
The synthetic method of a kind of tyrosine kinase inhibitor PCI-32765 of the present invention; can suppress the Tyrosylprotein kinase as B cell principal recipient signal; generation and the toxic side effect that can not only suppress hemocyte are less; and reaction conditions is gentle; simple to operate, be convenient to purifying, with low cost; environmental friendliness is fit to large-scale production.
The above is only embodiments of the invention; not thereby limit the scope of the claims of the present invention; every equivalent structure or equivalent flow process conversion that utilizes description of the present invention to do; or directly or indirectly be used in other relevant technical fields, all in like manner be included in scope of patent protection of the present invention.
Claims (4)
1. the synthetic method of a tyrosine kinase inhibitor PCI-32765, it is characterized in that: its synthetic method comprises the following steps:
1), alkaline reagents deposit with the catalyzer existence condition under, in suitable solvent, compound 10(3-bromo-3H-pyrazolo [3,4-d] pyrimidine-4-amine) obtain compound 6(3-(4-phenoxy phenoxy)-1H-pyrazolo [3,4-d] pyrimidine-4-amine with compound 15 alkaline reagents generation linked reactions);
2), compound 6(3-(4-phenoxy phenoxy)-1H-pyrazolo [3,4-d] pyrimidine-4-amine) obtain compound 11((R with compound 16 basic catalyst reactions)-3-(4-amino-3-(4-phenoxy phenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-yl) piperidines-1-carboxylic acid tert-butyl ester);
3), compound 11((R)-3-(4-amino-3-(4-phenoxy phenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-yl) piperidines-1-carboxylic acid tert-butyl ester) obtain compound 12((R by protection)-3-(3-(4-phenoxy phenyl)-4-(2,2,2-trifluoroacetyl amido)-1H-pyrazolo [3,4-d] pyrimidine-1-yl) piperidines-1-carboxylic acid tert-butyl ester);
4), compound 12((R)-3-(3-(4-phenoxy phenyl)-4-(2,2,2-trifluoroacetyl amido)-1H-pyrazolo [3,4-d] pyrimidine-1-yl) piperidines-1-carboxylic acid tert-butyl ester) the selectivity deprotection obtains compound 13((R)-2,2,2-three fluoro-N-(3-(4-phenoxy phenyl)-1-(piperidines-3-yl)-1H-pyrazolo [3,4-d] pyrimidine-4-yl) ethanamide);
5), compound 13((R)-2,2,2-three fluoro-N-(3-(4-phenoxy phenyl)-1-(piperidines-3-yl)-1H-pyrazolo [3,4-d] pyrimidine-4-yl) ethanamide) remaining unique position for compound 17 solvent attacks only, obtain very pure compound 14((R)-N-(1-(1-propionyl acylpiperidine-3-yl)-3-(4-phenoxy phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-yl)-2,2, the 2-trifluoroacetamide);
6), compound 14((R)-N-(1-(1-propionyl acylpiperidine-3-yl)-3-(4-phenoxy phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-yl)-2,2, the 2-trifluoroacetamide) take off protecting group and obtain PCI-32765.
2. the synthetic method of a kind of tyrosine kinase inhibitor PCI-32765 according to claim 1, it is characterized in that: described step 1) compound 15 alkaline reagentss can be selected cesium carbonate, salt of wormwood, sodium carbonate, sodium bicarbonate, sodium phosphate, potassiumphosphate, potassiumphosphate, sodium-acetate, Potassium ethanoate, wherein the activity with Potassium ethanoate is the strongest; Catalyzer can use PdCl2 (PPh3) 2, PdCl2-Mn (OAc) 2, Pd (TMHD) 2, PdCl2 (PhCN) 2, Pd (dppf) 2Cl2, has best catalytic effect; Solvent can be selected aprotic solvent, comprises ethers, as THF, and Isosorbide-5-Nitrae-dioxane etc.; Polar aprotic solvent is as DMSO, DMF, NMP etc.; The preferred 40-90 of temperature of reaction ℃.
3. the synthetic method of a kind of tyrosine kinase inhibitor PCI-32765 according to claim 1, it is characterized in that: described step 2), compound 16 basic catalysts are mineral alkalis, can react smoothly under the mineral alkali catalytic condition, described mineral alkali can be selected cesium carbonate, salt of wormwood, sodium carbonate, sodium bicarbonate, sodium phosphate, potassiumphosphate, potassiumphosphate, sodium-acetate, Potassium ethanoate, wherein best with the effect of cesium carbonate; The solvent system selection ethers is such as ether, isopropyl ether, methyl tertiary butyl ether, THF etc.; Temperature range is 30-80 ℃.
4. the synthetic method of a kind of tyrosine kinase inhibitor PCI-32765 according to claim 1, it is characterized in that: described step 3) is first protected amino, makes subsequent reactions have specificity, prevents the generation of by product; Make acid binding agent with organic bases triethylamine, diisopropylethylamine, pyridine, two cyclohexyl amines, solvent can be ethers and halogenated hydrocarbon, can complete this reaction under room temperature.
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