CN105820168A - Preparation method of Ibrutinib intermediate - Google Patents
Preparation method of Ibrutinib intermediate Download PDFInfo
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Abstract
The invention discloses a preparation method of an Ibrutinib intermediate shown as a formula 4. The method comprises the following steps: in a organic solvent, under effect of an acid-binding agent, a compound shown as a formula 2 and a compound shown as a formula 3 are subjected to a nucleophilic substitution reaction, and the Ibrutinib intermediate shown as the formula 4 is prepared. The acid-binding agent is one or more of sodium carbonate, potash and sodium hydride; wherein, Y is C1-C6 alkyl, phenyl or C1-C6 alkyl-substituted phenyl; and Z is halogen, or 4-phenoxyl-phenyl. The preparation method has the advantages of simple operation, low cost, less reagent amount, less three wastes, environmental pollution, simple post-treatment, high yield, and high optical purity, and is suitable for industrial production.
Description
Technical field
The present invention is specifically related to a kind of preparation method replacing Buddhist nun's intermediate according to Shandong.
Background technology
Antitumor drug replaces Buddhist nun (Ibrutinib) according to Shandong, its chemical entitled 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base]-piperidino]-2-propylene-1-ketone, molecular formula is C25H24N6O2, indication is lymphoma mantle cell and chronic lymphocytic leukemia, and structural formula is as follows:
According to Shandong for Buddhist nun
United States Patent (USP) US20080108636 discloses according to Shandong for Buddhist nun and preparation method thereof.Synthetic route is as follows:
Which disclose one according to Shandong for Buddhist nun's intermediate (R)-1-tertbutyloxycarbonyl-3-(4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base) preparation method of piperidines: with intermediate (3) with (S)-1-Boc-3-hydroxy piperidine as raw material, reaction (Mitsunobu reaction) is prolonged through light, obtaining intermediate (4), yield is only 34.0%.
According to Shandong for Buddhist nun's intermediate (R)-1-tertbutyloxycarbonyl-3-(4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3 disclosed in both at home and abroad, 4-d] pyrimidine-1-base) piperidines only has above-mentioned report, and the method makes to use up prolongs reaction and there is shortcomings: Polymer-Supported triphenylphosphine is expensive；Reagent dosage is big, and the three wastes produce more；Operation is complicated；Post-reaction treatment demand pole chromatography purification；Route yield is low, and cost is high.Be not suitable for large-scale industrial production in this way.
United States Patent (USP) US20110230476 and US8673925 disclose intermediate 3-iodo-1H-pyrazoles [3,4-d] pyrimidine-4-amine and (S)-1-t-butoxycarbonyl-piperidin-3-base-4-methyl isophthalic acid-active ester carry out nucleophilic substitution, but this report employs the cesium carbonate of costliness, and reaction yield 30%, post processing need to use column chromatography method, and the optical purity of product is poor.
For better meeting pharmacy needs, the method that developing low-cost, yield are high has higher practical commercial value, the most more meets the requirement of Green Chemistry.It is therefore desirable to seek simple to operate, low cost, reagent dosage are few, the few environmental friendliness of the three wastes, post processing is simple, yield is high, optical purity is high, be suitable for intermediate (R)-1-tertbutyloxycarbonyl-3-(4-amino-3-(4-the Phenoxyphenyl)-1H-pyrazolo [3 of industrialized production, 4-d] pyrimidine-1-base) piperidines preparation method, to overcome the many defects in prior art.
Summary of the invention
The technical problem to be solved in the present invention is to replace Buddhist nun's intermediate (R)-1-tertbutyloxycarbonyl-3-(4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3 in order to overcome in prior art according to Shandong, 4-d] pyrimidine-1-base) the preparation method cost of piperidines is high, reagent dosage big, the three wastes produce more, operation is complicated, post processing is loaded down with trivial details, yield is low, optical purity is low, be not suitable for the defect of industrialized production, and provide a kind of according to Shandong for the preparation method of Buddhist nun's intermediate.The present invention simple to operate for the preparation method of Buddhist nun's intermediate according to Shandong, low cost, reagent dosage are few, the few environmental friendliness of the three wastes, post processing is simple, yield is high, optical purity is high, be suitable for industrialized production.
The invention provides a kind of preparation method replacing Buddhist nun's intermediate according to Shandong as shown in Equation 4, it comprises the steps: in organic solvent, under the effect of acid binding agent, compound as shown in Equation 2 and compound as shown in Equation 3 are carried out nucleophilic substitution, prepare as shown in Equation 4 according to Shandong for Buddhist nun's intermediate,；Described acid binding agent is one or more in sodium carbonate, potassium carbonate and sodium hydride；
Wherein, described Y is C1～C6Alkyl, phenyl or " C1～C6The substituted phenyl of alkyl "；Described Z is halogen, or 4-Phenoxy-phenyl.
Described C1～C6The preferred C of alkyl1～C3Alkyl.
Described C1～C6C described in the substituted phenyl of alkyl1～C6The preferred C of alkyl1～C3Alkyl.
Described C1～C3The preferred methyl of alkyl.
The preferred fluorine of described halogen, chlorine, bromine or iodine；More preferably iodine.
Described C1～C6The substituted phenyl of alkyl preferred 4-methylphenyl.
Described as shown in Equation 4 according in the preparation method for Buddhist nun's intermediate of the Shandong, described organic solvent can various organic solvents used by routine in this type of nucleophilic substitution of this area, in the present invention, preferably aprotic, polar kind solvent.One or more in described aprotic, polar kind solvent preferred amide kind solvent, sulfoxide type solvents and nitrile solvents.The preferred N,N-dimethylformamide of described amide solvent.The preferred dimethyl sulfoxide of described sulfoxide type solvents.The preferred acetonitrile of described nitrile solvents.
Described as shown in Equation 4 according in the preparation method for Buddhist nun's intermediate of the Shandong, the volume mass ratio preferably 5 mls/g～100 mls/g of described organic solvent and described compound as shown in Equation 3, more preferably 10 mls/g～50 mls/g.
Described acid binding agent can be one or more in sodium carbonate, potassium carbonate and sodium hydride, preferably sodium carbonate.
In the described preparation method replacing Buddhist nun's intermediate according to Shandong as shown in Equation 4, in described nucleophilic substitution, it is also preferred that the left the mol ratio of described compound as shown in Equation 3 and described compound as shown in Equation 2 is 1:1～1:4；Such as 1:1～1:2；The most such as 1:1～1:1.25.
In the described preparation method replacing Buddhist nun's intermediate according to Shandong as shown in Equation 4, in described nucleophilic substitution, it is also preferred that the left the mol ratio of described compound as shown in Equation 3 and described acid binding agent is 1:1～1:5, such as 1:2～1:4.
In the described preparation method replacing Buddhist nun's intermediate according to Shandong as shown in Equation 4, the temperature of described nucleophilic substitution preferably 60 DEG C～160 DEG C, more preferably 85 DEG C～160 DEG C, such as 100 DEG C～120 DEG C.
In the described preparation method replacing Buddhist nun's intermediate according to Shandong as shown in Equation 4, the process of described nucleophilic substitution can use the traditional test methods (such as TLC, HPLC, GC or NMR) in this area to be monitored, typically using compound as shown in Equation 3 disappear time as reaction end, the time of described nucleophilic substitution is preferably 4～24 hours or more, more preferably 6～12 hours, most preferably 8～10 hours.
The described preparation method replacing Buddhist nun's intermediate according to Shandong as shown in Equation 4, at described nucleophilic substitution after end, it is preferred that also can further include the operation of post processing.The method of described post processing and condition can be method and the condition of this type of nucleophilic substitution post processing routine of this area, preferably: reaction system is mixed after terminating by reaction with water, filter,.Described reaction system is mixed with water in the method for mixing preferably stir.The preferably 2～4 hours time of described stirring.Described reaction system is mixed with water in water and described organic solvent volume ratio preferably (3～5): 1, more preferably 4:1.Described reaction system being mixed with water preferably adds water in reaction system.Described adding water preferably drips water.
Described as shown in Equation 4 according to Shandong for the preparation method of Buddhist nun's intermediate, prepare as shown in Equation 4 according to Shandong for Buddhist nun's intermediate after, it is preferred that also include the step of purifying products.The preferred recrystallization of step of described purifying products.The preferred esters solvent of atent solvent that described recrystallization is used and/or aromatic hydrocarbon solvent.Described esters solvent ethyl acetate.The preferred toluene of described aromatic hydrocarbon solvent.
The described preparation method replacing Buddhist nun's intermediate according to Shandong as shown in Equation 4, preferably, also comprise the steps of: described compound as shown in Equation 2 is joined in the mixture of described compound as shown in Equation 3, described acid binding agent and described organic solvent, carry out described nucleophilic substitution,.More preferably, the temperature of the mixture of described compound as shown in Equation 3, described acid binding agent and described organic solvent is 30 DEG C～50 DEG C.The method that the hybrid mode of the mixture of described compound as shown in Equation 3, described acid binding agent and described organic solvent is preferably used stirring, more preferably stirring 20 minutes～40 minutes.
The described preparation method replacing Buddhist nun's intermediate according to Shandong as shown in Equation 4, preferably, further comprise following steps: at a temperature of 0 to 30 DEG C, in organic solvent, under the effect of organic base, compound as shown in Equation 5 and compound as shown in Equation 6 are carried out esterification, prepares described compound as shown in Equation 2；
Wherein, described Y is ditto described.
One or more in the described alkane solvents of the preferred halogen substiuted of organic solvent, esters solvent, aromatic hydrocarbon solvent and azepine aromatic hydrocarbon solvent in described esterification.The preferred dichloromethane of alkane solvents of described halogen substiuted and/or chloroform.Described esters solvent ethyl acetate.The preferred benzene of described aromatic hydrocarbon solvent and/or toluene, the described preferred pyridine of azepine aromatic hydrocarbon solvent.
The volume mass ratio preferably 2 mls/g～15 mls/g of the described organic solvent in described esterification and described compound as shown in Equation 5, more preferably 4 mls/g～10 mls/g.
One or more in the organic bases such as the preferred pyridines of described organic base, imidazoles, Pyrazine, indoles, fast quinoline class, tertiary amines, phenyl amines.The described preferred triethylamine of tertiary amines organic base and/or N, N-diisopropylethylamine.The described preferred N of phenyl amines organic base, accelerine.One or more in the described preferred pyridine of pyridines organic base, picoline, DMAP and 2-methyl-5-ethylpyridine.
When described organic base is pyridines organic base, described pyridines organic base can also be the organic solvent of described esterification.
Described compound as shown in Equation 5 and the mol ratio preferred 1:(1.5～10 of described organic base), more preferably 1:(2～5).
Described compound as shown in Equation 5 and the mol ratio preferred 1:(0.7～1.5 of described compound as shown in Equation 6), more preferably 1:(0.9～1.2).
The temperature of described esterification preferably 15 DEG C～25 DEG C.
The process of described esterification can use the traditional test methods (such as TLC, HPLC, GC or NMR) in this area to be monitored, typically using compound as shown in Equation 5 disappear time as reaction end, the time of described esterification is preferably 5 hours～12 hours.
Described esterification is after end, it is preferred that also can further include the operation of post processing.The method of described post processing and condition can be the conventional method of this type of post-reaction treatment of this area and condition, preferably: after reaction terminates, extract, wash, concentrate, organic solvent pull an oar, filter, wash, dry,.Described extraction is preferably used esters solvent and extracts.Described esters solvent ethyl acetate.Described washing after described extraction is preferably used water, dilute hydrochloric acid, saline solution wash successively.The preferred concentrating under reduced pressure of described concentration.The described preferred petroleum ether of organic solvent in organic solvent making beating.Described precipitation preferably precipitates under conditions of stirring.Described washing after described filtration is preferably used petroleum ether and washs.Described being dried preferably is dried, and more preferably dries under the conditions of 60 DEG C.
The described preparation method replacing Buddhist nun's intermediate according to Shandong as shown in Equation 4, it is also preferred that the left also can further include following steps: compound as shown in Equation 6 is joined in the mixture of described compound as shown in Equation 5, described organic base and described organic solvent.The temperature of described mixture preferably 3 DEG C～8 DEG C, more preferably 4 DEG C～5 DEG C.The mode of the addition of the described compound shown in formula 6 preferably drips or is dividedly in some parts.
The invention still further relates to the preparation method of a kind of compound as shown in Equation 2, it comprises the steps of: in organic solvent, under the effect of organic base, compound as shown in Equation 5 and compound as shown in Equation 6 are carried out esterification, prepare described compound as shown in Equation 2；
Wherein, described Y is ditto described.The condition of the method for described esterification is ditto described.
The described preparation method replacing Buddhist nun's intermediate according to Shandong as shown in Equation 4; preferably; after preparing described compound as shown in Equation 4, the compound shown in described formula 4 also can be further used for the compound prepared as shown in Equation 1, concrete; comprise the steps of: in organic solvent; at 0 DEG C～60 DEG C, in acid condition, compound as shown in Equation 4 carries out removing the reaction of amino protecting group; prepare described compound as shown in Equation 1,；Described Z is ditto described.
In the reaction of described removing amino protecting group, the crude product of the compound as shown in Equation 4 obtained by described nucleophilic substitution can direct plunge into the reaction of described removing amino protecting group and react.
In the reaction of described removing amino protecting group, described organic solvent can various organic solvents used by routine during this type of removes the reaction of amino protecting group for this area, in the present invention, preferably ether organic solvent and/or alcohol organic solvent.The preferred oxolane of described ether organic solvent and/or dioxane.The preferred methanol of described alcohol organic solvent and/or ethanol.
In the reaction of described removing amino protecting group, described acid condition is preferably to realize under the effect of hydrogen chloride.Described hydrogen chloride can be to be the form use with hydrochloride aqueous solution or hydrogen chloride organic solution.The concentration of the hydrogen chloride in described hydrochloride aqueous solution or hydrogen chloride organic solution is preferably 3mol/L～5mol/L, more preferably 4mol/L～4.5mol/L.Described hydrogen chloride and preferred 5:1～30:1 of mol ratio, more preferably 10:1～20:1 of described compound as shown in Equation 4.
The process of the reaction of described removing amino protecting group can use the traditional test methods (such as TLC, HPLC, GC or NMR) in this area to be monitored; it is preferably 5～12 hours as reaction end, the time of described removing amino protecting group reaction when typically disappearing using compound as shown in Equation 4.
The compound as shown in Equation 1 of the present invention is used as preparing the intermediate replacing Buddhist nun according to Shandong, and concrete preparation method can be found in United States Patent (USP) US20080108636.
In the present invention, represent tertiary butyl oxycarbonyl at the chemical group boc in formula 2, formula 4 and the compound shown in formula 5.
Heretofore described room temperature refers to that ambient temperature is 10～30 DEG C.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can combination in any, obtain the preferred embodiments of the invention.
Agents useful for same of the present invention and raw material are the most commercially.
The actively progressive effect of the present invention is: the present invention simple to operate for the preparation method of Buddhist nun's intermediate according to Shandong, low cost, reagent dosage are few, the few environmental friendliness of the three wastes, post processing is simple, yield is high, be suitable for industrialized production.
Detailed description of the invention
Further illustrate the present invention below by the mode of embodiment, but the most therefore limit the present invention among described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or selects according to catalogue.
In following example, chirality HPLC purity uses normalization method to detect and calculate: chromatographic column: LuxCellulose-1 chiral column (4.6mm × 250mm, 5 μm)；Flowing phase: normal hexane-ethanol (volume ratio 85:15)；Flow velocity: 0.8mL/min；Detection wavelength: 230nm；Column temperature: 30 DEG C.
Embodiment 1
In 100ml reaction bulb, add (S)-1-Boc-3-hydroxy piperidine (5.0g, 24.9mmol) and pyridine 20ml, ice bath is cooled to about 5 DEG C, add paratoluensulfonyl chloride (5.2g, 27.4mmol), stirred overnight at room temperature in four batches.Reactant liquor adds ethyl acetate, organic phase washed with water, dilute hydrochloric acid (3M), brine It, concentrating under reduced pressure, residue adds petroleum ether 20ml, stirs 2.0h, filter, petroleum ether, 60 DEG C of drying, obtain white crystal product (S)-1-t-butoxycarbonyl-piperidin-3-base-4-methyl isophthalic acid-benzene sulfonate (8.5g), yield 96%, specific rotatory power: [α]20 D=-24.6 ° (c=1.0, EtOH).
Embodiment 2
In 100ml reaction bulb, add (S)-1-Boc-3-hydroxy piperidine (5.0g, 24.9mmol), triethylamine (5.0g, 49.5mmol) with dichloromethane 50ml, ice bath is cooled to about 5 DEG C, mesyl chloride (3.15g, 27.4mmol), stirred overnight at room temperature is dripped in reactant liquor.Organic facies brine It, concentrating under reduced pressure, residue adds petroleum ether 20ml, stirring 2.0h, filters, petroleum ether, 60 DEG C of drying, obtain white crystal product (S)-1-t-butoxycarbonyl-piperidin-3-base-methanesulfonates (6.4g), yield 92%, specific rotatory power: [α]20 D=-16.3 ° (c=1.0, EtOH).
Embodiment 3
In 100ml reaction bulb, add (S)-1-Boc-3-hydroxy piperidine (5.0g, 24.9mmol), diisopropylethylamine (6.4g, 49.5mmol) with ethyl acetate 50ml, ice bath is cooled to about 5 DEG C, mesyl chloride (3.15g, 27.4mmol), stirred overnight at room temperature is dripped in reactant liquor.Organic facies brine It, concentrating under reduced pressure, residue adds petroleum ether 20ml, stirring 2.0h, filter, petroleum ether, 60 DEG C of drying, obtain white crystal product (S)-1-t-butoxycarbonyl-piperidin-3-base-methanesulfonates (6.6g), yield 95% specific rotatory power: [α]20 D=-16.4 ° (c=1.0, EtOH).
Embodiment 4
In 100ml reaction bulb, it is sequentially added into intermediate 3 (5.0g, 16.5mmol), DMF (50ml) and sodium hydride (1.2g, 49.5mmol), 40 DEG C of stirring 0.5h, add (S)-1-t-butoxycarbonyl-piperidin-3-base-4-methyl isophthalic acid-benzene sulfonate (7.3g, 20.6mmol), in 90 DEG C of stirring reaction 8.0h.Water 200ml is dripped in reactant liquor, stirring 2.0h, separate out faint yellow solid, filter, obtain midbody compound 4 crude product (5.7g), through re crystallization from toluene, obtain white solid (5.2g), yield 65%, chirality HPLC purity 96.3% (S-content of isomer 1.4%), specific rotatory power: [α]20 D=-18.5 ° (c=1.0, EtOH)
Embodiment 5
In 100ml reaction bulb, it is sequentially added into intermediate 3 (5.0g, 16.5mmol), DMF (50ml) and potassium carbonate (6.8g, 49.5mmol), 40 DEG C of stirring 0.5h, add (S)-1-t-butoxycarbonyl-piperidin-3-base-4-methyl isophthalic acid-benzene sulfonate (7.3g, 20.6mmol), in 100 DEG C of stirring reaction 6.0h.Water 200ml is dripped in reactant liquor, stirring 2.0h, separate out faint yellow solid, filter, obtain midbody compound 4 crude product (6.1g), through re-crystallizing in ethyl acetate, obtain white solid (5.5g), yield 69%, chirality HPLC purity 97.5% (S-content of isomer 1.2%).Specific rotatory power: [α]20 D=-18.6 ° (c=1.0, EtOH).
Embodiment 6
In 100ml reaction bulb, it is sequentially added into intermediate 3 (5.0g, 16.5mmol), DMF (50ml) and sodium carbonate (5.3g, 49.5mmol), 40 DEG C of stirring 0.5h, add (S)-1-t-butoxycarbonyl-piperidin-3-base-4-methyl isophthalic acid-benzene sulfonate (7.3g, 20.6mmol), in 120 DEG C of stirring reaction 24.0h.In reactant liquor, drip water 200ml, stir 2.0h, separate out faint yellow solid, filter, obtain midbody compound 4 crude product (5.4g), through re crystallization from toluene, obtain white solid (5.0g), yield 62%, chirality HPLC purity 96.4% (S-content of isomer 1.5%).Specific rotatory power: [α]20 D=-18.3 ° (c=1.0, EtOH).
Embodiment 7
In 100ml reaction bulb, it is sequentially added into intermediate 3 (5.0g, 16.5mmol), DMSO (50ml) and potassium carbonate (6.8g, 49.5mmol), 40 DEG C of stirring 0.5h, add (S)-1-t-butoxycarbonyl-piperidin-3-base-4-methyl isophthalic acid-benzene sulfonate (7.3g, 20.6mmol), in 160 DEG C of stirring reaction 4.0h.In reactant liquor, drip water 200ml, stir 2.0h, separate out faint yellow solid, filter, obtain midbody compound 4 crude product (5.5g), through re crystallization from toluene, obtain white solid (5.1g), yield 64%, chirality HPLC purity 97.5% (S-content of isomer 1.2%).Specific rotatory power: [α]20 D=-18.5 ° (c=1.0, EtOH).
Embodiment 8
In 100ml reaction bulb, it is sequentially added into intermediate 3 (5.0g, 16.5mmol), acetonitrile (50ml) and potassium carbonate (6.8g, 49.5mmol), 40 DEG C of stirring 0.5h, add (S)-1-t-butoxycarbonyl-piperidin-3-base-4-methyl isophthalic acid-benzene sulfonate (7.3g, 20.6mmol), in 85 DEG C of stirring reaction 24.0h.In reactant liquor, drip water 200ml, stir 2.0h, separate out faint yellow solid, filter, obtain midbody compound 4 crude product (5.2g), through re crystallization from toluene, obtain white solid (4.7g), yield 59%, chirality HPLC purity 97.5% (S-content of isomer 1.6%).Specific rotatory power: [α]20 D=-18.2 ° (c=1.0, EtOH).
Embodiment 9
In 100ml reaction bulb, it is sequentially added into intermediate 3 (5.0g, 16.5mmol), DMF (50ml) and potassium carbonate (6.8g, 49.5mmol), 40 DEG C of stirring 0.5h, add (S)-1-t-butoxycarbonyl-piperidin-3-base-4-methyl isophthalic acid-benzene sulfonate (7.3g, 20.6mmol), in 50 DEG C of stirring reaction 48.0h.Water 200ml is dripped in reactant liquor, stirring 2.0h, separate out faint yellow solid, filter, obtain midbody compound 4 crude product (4.2g), through re-crystallizing in ethyl acetate, obtain white solid (3.8g), yield 47%, chirality HPLC purity 97.3% (S-content of isomer 2.0%).Specific rotatory power: [α]20 D=-17.5 ° (c=1.0, EtOH).
Embodiment 10
In 100ml reaction bulb, it is sequentially added into 3-iodo-1H-pyrazoles [3,4-d] pyrimidine-4-amine (4.3g, 16.5mmol), DMF (50ml) and potassium carbonate (6.8g, 49.5mmol), 40 DEG C of stirring 0.5h, add (S)-1-t-butoxycarbonyl-piperidin-3-base-4-methyl isophthalic acid-benzene sulfonate (7.3g, 20.6mmol), in 120 DEG C of stirring reaction 6.0h.Water 200ml is dripped in reactant liquor, stirring 2.0h, separate out faint yellow solid, filter, obtain intermediate (R)-1-tertbutyloxycarbonyl-3-(4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidine-1-base) piperidines crude product (5.4g), through re crystallization from toluene, obtain faint yellow solid (4.9g), yield 67%, chirality HPLC purity 97.6% (S-content of isomer 1.2%).Specific rotatory power: [α]20 D=-26.5 ° (c=1.0, EtOH).
Embodiment 11
In 100ml reaction bulb, it is sequentially added into 3-bromo-1H-pyrazoles [3,4-d] pyrimidine-4-amine (3.5g, 16.5mmol), DMF (50ml) and potassium carbonate (6.8g, 49.5mmol), 40 DEG C of stirring 0.5h, add (S)-1-t-butoxycarbonyl-piperidin-3-base-4-methyl isophthalic acid-benzene sulfonate (7.3g, 20.6mmol), in 120 DEG C of stirring reaction 8.0h.Water 200ml is dripped in reactant liquor, stirring 2.0h, separate out faint yellow solid, filter, obtain intermediate (R)-1-tertbutyloxycarbonyl-3-(4-amino-3-bromo-1H-pyrazolo [3,4-d] pyrimidine-1-base) piperidines crude product (4.8g), through re-crystallizing in ethyl acetate, obtain faint yellow solid (4.3g), yield 65%, chirality HPLC purity 97.8% (S-content of isomer 1.1%).Specific rotatory power: [α]20 D=-23.6 ° (c=1.0, EtOH).
Comparative example 1
In 100ml reaction bulb, it is sequentially added into intermediate 3 (5.0g, 16.5mmol), DMF (50ml) and cesium carbonate (16.1g, 49.5mmol), 40 DEG C of stirring 24h, add (S)-1-t-butoxycarbonyl-piperidin-3-base-4-methyl isophthalic acid-benzene sulfonate (7.3g, 20.6mmol), in 100 DEG C of stirring reaction 6.0h.Water 200ml is dripped in reactant liquor, stirring 2.0h, separate out faint yellow solid, filter, obtain midbody compound 4 crude product (3.4g), through re-crystallizing in ethyl acetate, obtain white solid (3.1g), yield 38%, chirality HPLC purity 97.4% (S-content of isomer 1.8%).Specific rotatory power: [α]20 D=-17.7 ° (c=1.0, EtOH).
Claims (10)
1. the preparation method replacing Buddhist nun's intermediate according to Shandong as shown in Equation 4, it is characterized in that, it comprises the steps: in organic solvent, under the effect of acid binding agent, compound as shown in Equation 2 and compound as shown in Equation 3 are carried out nucleophilic substitution, prepare as shown in Equation 4 according to Shandong for Buddhist nun's intermediate,；Described acid binding agent is one or more in sodium carbonate, potassium carbonate and sodium hydride；
Wherein, described Y is C1～C6Alkyl, phenyl or " C1～C6The substituted phenyl of alkyl "；Described Z is halogen, or 4-Phenoxy-phenyl.
2. the preparation method replacing Buddhist nun's intermediate according to Shandong the most as shown in Equation 4, it is characterised in that described C1～C6Alkyl is C1～C3Alkyl；
And/or, described C1～C6C described in the substituted phenyl of alkyl1～C6Alkyl is C1～C3Alkyl；
And/or, described halogen is fluorine, chlorine, bromine or iodine；
And/or, described organic solvent is aprotic, polar kind solvent；
And/or, described organic solvent is 5 mls/g～100 mls/g with the volume mass ratio of described compound as shown in Equation 3.
3. the preparation method replacing Buddhist nun's intermediate according to Shandong the most as shown in Equation 4, it is characterised in that described C1～C3Alkyl is methyl；
And/or, described halogen is iodine；
And/or, described aprotic, polar kind solvent is one or more in amide solvent, sulfoxide type solvents and nitrile solvents；
And/or, described organic solvent is 10 mls/g～50 mls/g with the volume mass ratio of described compound as shown in Equation 3.
4. the preparation method replacing Buddhist nun's intermediate according to Shandong the most as shown in Equation 4, it is characterised in that described amide solvent is DMF；Described sulfoxide type solvents is dimethyl sulfoxide；Described nitrile solvents is acetonitrile.
5. the preparation method replacing Buddhist nun's intermediate according to Shandong the most as shown in Equation 4, it is characterised in that in described nucleophilic substitution, the mol ratio of described compound as shown in Equation 3 and described compound as shown in Equation 2 is 1:1～1:4；
And/or, in described nucleophilic substitution, described compound as shown in Equation 3 and the mol ratio of described acid binding agent are 1:1～1:5.
6. the preparation method replacing Buddhist nun's intermediate according to Shandong the most as shown in Equation 4, it is characterised in that in described nucleophilic substitution, the mol ratio of described compound as shown in Equation 3 and described compound as shown in Equation 2 is 1:1～1:2；
And/or, in described nucleophilic substitution, described compound as shown in Equation 3 and the mol ratio of described acid binding agent are 1:2～1:4.
7. the preparation method replacing Buddhist nun's intermediate according to Shandong the most as shown in Equation 4, it is characterised in that the temperature of described nucleophilic substitution is 85 DEG C～160 DEG C；
And/or, the time of described nucleophilic substitution is 4～24 hours；
And/or, the described preparation method replacing Buddhist nun's intermediate according to Shandong as shown in Equation 4, at described nucleophilic substitution after end, further comprise the operation of post processing；Described post processing is: reaction system is mixed after terminating by reaction with water, filters,；
And/or, described as shown in Equation 4 according to Shandong for the preparation method of Buddhist nun's intermediate, prepare as shown in Equation 4 according to Shandong for Buddhist nun's intermediate after, also include the step of purifying products.
8. the preparation method replacing Buddhist nun's intermediate according to Shandong the most as shown in Equation 4, it is characterised in that the temperature of described nucleophilic substitution is 100 DEG C～120 DEG C；
And/or, in the described preparation method replacing Buddhist nun's intermediate according to Shandong as shown in Equation 4, the time of described nucleophilic substitution is 6～12 hours；
And/or, the step of described purifying products is recrystallization.
9. the preparation method replacing Buddhist nun's intermediate according to Shandong the most as shown in Equation 4, it is characterized in that, the described preparation method replacing Buddhist nun's intermediate according to Shandong as shown in Equation 4, also comprise the steps of: described compound as shown in Equation 2 is joined in the mixture of described compound as shown in Equation 3, described acid binding agent and described organic solvent, carry out described nucleophilic substitution,.
10. the preparation method replacing Buddhist nun's intermediate according to Shandong the most as shown in Equation 4, it is characterised in that the temperature of the mixture of described compound as shown in Equation 3, described acid binding agent and described organic solvent is 30 DEG C～50 DEG C.
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| CN107014943A (en) * | 2017-06-07 | 2017-08-04 | 福建省微生物研究所 | It is a kind of according to Shandong replace Buddhist nun's enantiomter detection method |
| CN116063309A (en) * | 2023-03-13 | 2023-05-05 | 北京京卫燕康药物研究所有限公司 | Synthesis method of ibrutinib |
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| CN102887900A (en) * | 2006-09-22 | 2013-01-23 | 药品循环公司 | Inhibitors of bruton's tyrosine kinase |
| CN103534258A (en) * | 2011-05-17 | 2014-01-22 | 普林斯匹亚生物制药公司 | Tyrosine kinase inhibitors |
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| CN103534258A (en) * | 2011-05-17 | 2014-01-22 | 普林斯匹亚生物制药公司 | Tyrosine kinase inhibitors |
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| CN107014943A (en) * | 2017-06-07 | 2017-08-04 | 福建省微生物研究所 | It is a kind of according to Shandong replace Buddhist nun's enantiomter detection method |
| CN116063309A (en) * | 2023-03-13 | 2023-05-05 | 北京京卫燕康药物研究所有限公司 | Synthesis method of ibrutinib |
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