CN105820168B - A kind of preparation method for replacing Buddhist nun's intermediate according to Shandong - Google Patents
A kind of preparation method for replacing Buddhist nun's intermediate according to Shandong Download PDFInfo
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- 0 **(CCC1)C[C@@]1[n](c1ncnc(CCC=C=*)c11)nc1C1=CC=C(*c2ccccc2)CC1 Chemical compound **(CCC1)C[C@@]1[n](c1ncnc(CCC=C=*)c11)nc1C1=CC=C(*c2ccccc2)CC1 0.000 description 5
Abstract
The invention discloses a kind of preparation methods that Buddhist nun's intermediate is replaced according to Shandong as shown in Equation 4, it includes the following steps: in organic solvent, under the action of acid binding agent, compound as shown in Equation 2 and compound as shown in Equation 3 are subjected to nucleophilic substitution, it is made as shown in Equation 4 and replaces Buddhist nun's intermediate according to Shandong；The acid binding agent is one of sodium carbonate, potassium carbonate and sodium hydride or a variety of；Wherein, the Y is C1~C6Alkyl, phenyl or " C1~C6Alkyl-substituted phenyl "；The Z is halogen or 4- Phenoxy-phenyl.It is of the invention according to Shandong for Buddhist nun's intermediate preparation method it is easy to operate, at low cost, reagent dosage is few, the three wastes it is few it is environmental-friendly, post-processing is simple, high income, optical purity are high, is suitable for industrialized production.
Description
Technical field
The present invention is specifically related to a kind of preparation method that Buddhist nun's intermediate is replaced according to Shandong.
Background technique
Anti-tumor drug replaces Buddhist nun (Ibrutinib) according to Shandong, entitled 1- [(3R) -3- [4- amino -3- (the 4- phenoxy group of chemistry
Phenyl) -1H- pyrazolo [3,4-d] pyrimidine -1- base] -1- piperidyl] -2- propylene -1- ketone, molecular formula C25H24N6O2, adapt to
Disease is lymphoma mantle cell and chronic lymphocytic leukemia, and structural formula is as follows:
Buddhist nun is replaced according to Shandong
United States Patent (USP) US20080108636 is disclosed according to Shandong for Buddhist nun and preparation method thereof.Synthetic route is as follows:
Which disclose one kind to replace Buddhist nun's intermediate (R) -1- tertbutyloxycarbonyl -3- (4- amino -3- (4- phenoxy group according to Shandong
Phenyl) -1H- pyrazolo [3,4-d] pyrimidine -1- base) piperidines preparation method: with intermediate (3) and (S) -1-Boc-3- hydroxyl
Piperidines is raw material, prolongs reaction (Mitsunobu reaction) by light, obtains intermediate (4), yield is only 34.0%.
It is disclosed both at home and abroad to replace Buddhist nun's intermediate (R) -1- tertbutyloxycarbonyl -3- (4- amino -3- (4- phenoxy group benzene according to Shandong
Base) -1H- pyrazolo [3,4-d] pyrimidine -1- base) piperidines only has above-mentioned report, and the method is prolonged reaction using light and is lacked there are many
Point: Polymer-Supported triphenylphosphine is expensive；Reagent dosage is big, and the three wastes generate more；Operation is complicated；Post-reaction treatment
Demand pole chromatographic purifying；Route yield is low, at high cost.Be not suitable for large-scale industrial production in this way.
It is phonetic that the iodo- 1H- pyrazoles [3,4-d] of intermediate 3- is disclosed in United States Patent (USP) US20110230476 and US8673925
Pyridine-4- amine and (S)-1- t-butoxycarbonyl-piperidin-3- base-4- methyl-1-active ester carry out nucleophilic substitution, but this report
Expensive cesium carbonate, and reaction yield 30% are used, post-processing need to use column chromatography method, and the optical purity of product is poor.
To better meet pharmacy needs, developing low-cost, the method for high income practical commercial value with higher,
More meet the requirement of Green Chemistry.It is therefore desirable to seek easy to operate, at low cost, reagent dosage is few, the three wastes it is few it is environmental-friendly,
Post-processing is simple, high income, optical purity are high, is suitable for intermediate (R) -1- tertbutyloxycarbonyl -3- (4- ammonia of industrialized production
Base -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine -1- base) piperidines preparation method, to overcome in the prior art
Many defects.
Summary of the invention
The technical problem to be solved by the present invention is to replace the tertiary fourth oxygen of Buddhist nun's intermediate (R) -1- according to Shandong in the prior art to overcome
The preparation method cost of carbonyl -3- (4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine -1- base) piperidines
High, reagent dosage is greatly, three wastes generation is more, operation is complicated, post-processing is cumbersome, yield is low, optical purity is low, is not suitable for work
The defect that industry metaplasia produces, and provide a kind of preparation method that Buddhist nun's intermediate is replaced according to Shandong.Of the invention replaces Buddhist nun's intermediate according to Shandong
Preparation method is easy to operate, at low cost, reagent dosage is few, the three wastes are environmental-friendly less, post-processing is simple, high income, optical purity
Height is suitable for industrialized production.
The present invention provides a kind of preparation methods that Buddhist nun's intermediate is replaced according to Shandong as shown in Equation 4 comprising following steps: has
In solvent, under the action of acid binding agent, compound as shown in Equation 2 and compound as shown in Equation 3 are subjected to nucleophilic displacement of fluorine
Reaction is made as shown in Equation 4 and replaces Buddhist nun's intermediate according to Shandong；The acid binding agent is in sodium carbonate, potassium carbonate and sodium hydride
It is one or more；
Wherein, the Y is C1~C6Alkyl, phenyl or " C1~C6Alkyl-substituted phenyl "；The Z is halogen, or
4- Phenoxy-phenyl.
The C1~C6The preferred C of alkyl1~C3Alkyl.
The C1~C6C described in alkyl-substituted phenyl1~C6The preferred C of alkyl1~C3Alkyl.
The C1~C3The preferred methyl of alkyl.
The preferred fluorine of the halogen, chlorine, bromine or iodine；More preferable iodine.
The C1~C6The alkyl-substituted preferred 4- methylphenyl of phenyl.
In the preparation method for replacing Buddhist nun's intermediate according to Shandong as shown in Equation 4, the organic solvent can be this field
Various organic solvents used in routine in such nucleophilic substitution, in the present invention, preferred aprotic, polar class solvent.Described
One of aprotic, polar class solvent preferred amide class solvent, sulfoxide type solvents and nitrile solvents are a variety of.The amide
The preferred N,N-dimethylformamide of class solvent.The preferred dimethyl sulfoxide of the sulfoxide type solvents.The preferred second of the nitrile solvents
Nitrile.
It is described it is as shown in Equation 4 according to Shandong in the preparation method of Buddhist nun's intermediate, the organic solvent and it is described as
Preferably 5 mls/g~100 mls/g of the volume mass ratio of 3 compound represented of formula, more preferable 10 mls/g~50 milliliters/
Gram.
The acid binding agent can be one of sodium carbonate, potassium carbonate and sodium hydride or a variety of, preferably sodium carbonate.
In the preparation method for replacing Buddhist nun's intermediate according to Shandong as shown in Equation 4, in the nucleophilic substitution, preferably
, the molar ratio of the compound as shown in Equation 3 and the compound as shown in Equation 2 is 1:1~1:4；Such as 1:1
~1:2；Such as 1:1~1:1.25 again.
In the preparation method for replacing Buddhist nun's intermediate according to Shandong as shown in Equation 4, in the nucleophilic substitution, preferably
, the molar ratio of the compound as shown in Equation 3 and the acid binding agent is 1:1~1:5, such as 1:2~1:4.
In the preparation method for replacing Buddhist nun's intermediate according to Shandong as shown in Equation 4, the temperature of the nucleophilic substitution
It is preferred that 60 DEG C~160 DEG C, more preferable 85 DEG C~160 DEG C, such as 100 DEG C~120 DEG C.
In the preparation method for replacing Buddhist nun's intermediate according to Shandong as shown in Equation 4, the process of the nucleophilic substitution
It can be monitored using the traditional test methods (such as TLC, HPLC, GC or NMR) in this field, generally with as shown in Equation 3
As reaction end when compound disappears, the time of the nucleophilic substitution is preferably 4~24 hours or more, more excellent
Select 6~12 hours, most preferably 8~10 hours.
The preparation method that Buddhist nun's intermediate is replaced according to Shandong as shown in Equation 4, is terminating in the nucleophilic substitution
Afterwards, preferably, also can further include the operation of post-processing.The method and condition of the post-processing can be the such parent in this field
The conventional method and condition of core substitution reaction post-processing, preferably: reaction system is mixed with water after reaction, is filtered,
?.It is described reaction system is mixed with water in mixed method preferably stir.The time of the stirring preferably 2~4
Hour.It is described reaction system is mixed with water in water and the organic solvent volume ratio preferably (3~5): 1, it is more excellent
Select 4:1.Described mix reaction system with water preferably adds water into reaction system.Water is preferably added dropwise in described plus water.
The preparation method that Buddhist nun's intermediate is replaced according to Shandong as shown in Equation 4 is replaced in Buddhist nun being made as shown in Equation 4 according to Shandong
After mesosome, preferably, further including the steps that purifying products.The step of described purifying products, preferably recrystallizes.The knot again
The preferred esters solvent of atent solvent used in crystalline substance and/or aromatic hydrocarbon solvent.The esters solvent ethyl acetate.Institute
The preferred toluene of the aromatic hydrocarbon solvent stated.
The preparation method that Buddhist nun's intermediate is replaced according to Shandong as shown in Equation 4, preferably, also comprising the following steps: by institute
The compound as shown in Equation 2 stated is added to the compound as shown in Equation 3, the acid binding agent and described organic molten
In the mixture of agent, the nucleophilic substitution is carried out.More preferably, the compound as shown in Equation 3, described
Acid binding agent and the organic solvent mixture temperature be 30 DEG C~50 DEG C.The compound as shown in Equation 3, institute
It is preferable to use the methods of stirring, more preferably 20 points of stirring for the hybrid mode of the mixture of the acid binding agent and the organic solvent stated
Clock~40 minute.
The preparation method that Buddhist nun's intermediate is replaced according to Shandong as shown in Equation 4, preferably, further comprising following step
It is rapid: 0 to 30 DEG C at a temperature of, in organic solvent, under the action of organic base, by compound as shown in Equation 5 and such as 6 institute of formula
The compound shown carries out esterification, and the compound as shown in Equation 2 is made；
Wherein, the Y is as described above.
Alkane solvents, the esters solvent, virtue that the preferred halogen of the organic solvent in the esterification replaces
One of hydrocarbon solvent and azepine aromatic hydrocarbon solvent are a variety of.The preferred methylene chloride of alkane solvents that the halogen replaces
And/or chloroform.The esters solvent ethyl acetate.The preferred benzene of the aromatic hydrocarbon solvent and/or toluene, it is described
The preferred pyridine of azepine aromatic hydrocarbon solvent.
The volume mass ratio of the organic solvent and the compound as shown in Equation 5 in the esterification
It is preferred that 2 mls/g~15 mls/g, more preferable 4 mls/g~10 mls/g.
The preferred pyridines of the organic base, imidazoles, Pyrazine, indoles, fast quinoline class, tertiary amines, phenyl amines etc. have
One of machine alkali is a variety of.The preferred triethylamine of tertiary amines organic base and/or N, N- diisopropylethylamine.The benzene
The preferred N of amine organic base, accelerine.The preferred pyridine of pyridines organic base, picoline, 4- dimethylamino pyrrole
One of pyridine and 2- methyl -5- ethylpyridine are a variety of.
When the organic base is pyridines organic base, it is anti-that the pyridines organic base is also possible to the esterification
The organic solvent answered.
Preferred 1:(1.5~10 of molar ratio of the compound as shown in Equation 5 and the organic base), more preferable 1:
(2~5).
The preferred 1:(0.7 of molar ratio of the compound as shown in Equation 5 and the compound as shown in Equation 6~
1.5), more preferable 1:(0.9~1.2).
Preferably 15 DEG C~25 DEG C of the temperature of the esterification.
The process of the esterification can using in this field traditional test methods (such as TLC, HPLC, GC or
NMR) be monitored, as reaction end when generally being disappeared using compound as shown in Equation 5, time of the esterification compared with
It goodly is 5 hours~12 hours.
The esterification after, preferably, also can further include the operation of post-processing.The post-processing
Method and condition can be such post-reaction treatment routine in this field method and condition, preferably: after reaction, extract
It takes, wash, being concentrated, organic solvent is beaten, is filtered, washed, dries.It is preferable to use esters solvent progress for the extraction
Extraction.The esters solvent ethyl acetate.Use of water is preferred for the washing after the extraction, dilute hydrochloric acid,
Saline solution is successively washed.The concentration is preferably concentrated under reduced pressure.Organic solvent in the organic solvent mashing is preferred
Petroleum ether.The precipitating is preferably precipitated under stirring conditions.The washing after the filtering preferably makes
It is washed with petroleum ether.The drying is preferably dried, and is more preferably dried under the conditions of 60 DEG C.
The preparation method that Buddhist nun's intermediate is replaced according to Shandong as shown in Equation 4, preferably, also can further include following step
It is rapid: compound as shown in Equation 6 is added to the compound as shown in Equation 5, the organic base and described organic
In the mixture of solvent.Preferably 3 DEG C~8 DEG C of the temperature of the mixture, more preferable 4 DEG C~5 DEG C.Shown in the formula 6
The mode of the addition of compound is preferably added dropwise or is added portionwise.
The invention further relates to a kind of preparation methods of compound as shown in Equation 2, and it includes following steps: organic solvent
In, under the action of organic base, compound as shown in Equation 5 and compound as shown in Equation 6 are subjected to esterification, institute is made
The compound as shown in Equation 2 stated；
Wherein, the Y is as described above.The condition of the method for the esterification is as described above.
The described preparation method that Buddhist nun's intermediate is replaced according to Shandong as shown in Equation 4, preferably, described such as 4 institute of formula being made
After the compound shown, also 4 compound represented of formula can be further used for prepare compound as shown in Equation 1, specifically
, it comprises the following steps: in organic solvent, at 0 DEG C~60 DEG C, in acid condition, compound as shown in Equation 4 being taken off
Except the reaction of amino protecting group, the compound as shown in Equation 1 is made；The Z is as described above.
In the reaction of the removing amino protecting group, change as shown in Equation 4 obtained by the nucleophilic substitution
The reaction that the crude product of conjunction object can direct plunge into the removing amino protecting group is reacted.
In the reaction of the removing amino protecting group, the organic solvent can be the such removing amido protecting in this field
Various organic solvents used in routine in the reaction of base, in the present invention, preferably ether organic solvent and/or alcohol organic solvent.
The preferred tetrahydrofuran of the ether organic solvent and/or dioxane.The preferred methanol of the alcohol organic solvent and/or second
Alcohol.
In the reaction of the removing amino protecting group, the acid condition is preferably real under the action of hydrogen chloride
It is existing.The hydrogen chloride can be to be used in the form of hydrochloride aqueous solution or hydrogen chloride organic solution.The hydrogen chloride water
The concentration of solution or the hydrogen chloride in hydrogen chloride organic solution is preferably 3mol/L~5mol/L, and more preferable 4mol/L~
4.5mol/L.Molar ratio preferred 5:1~30:1 of the hydrogen chloride and the compound as shown in Equation 4, more preferable 10:
1~20:1.
The process of the reaction of the described removing amino protecting group can using in this field traditional test methods (such as TLC,
HPLC, GC or NMR) it is monitored, as reaction end, the removing ammonia when generally being disappeared using compound as shown in Equation 4
The time of base protection group reaction is preferably 5~12 hours.
Compound as shown in Equation 1 of the invention is used as preparing the intermediate for replacing Buddhist nun according to Shandong, specific preparation method
It can be found in United States Patent (USP) US20080108636.
In the present invention, the chemical group boc in such as formula 2, formula 4 and 5 compound represented of formula indicates tertiary butyl oxycarbonyl.
Heretofore described room temperature refers to that environment temperature is 10~30 DEG C.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can any combination to get the present invention it is each preferably
Example.
The reagents and materials used in the present invention are commercially available.
The positive effect of the present invention is that: it is of the invention according to Shandong for Buddhist nun's intermediate preparation method it is easy to operate, at
This is low, reagent dosage is few, the three wastes are environmental-friendly less, post-processing is simple, high income, is suitable for industrialized production.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to the reality
It applies among a range.In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or according to quotient
The selection of product specification.
In following embodiment, chiral HPLC purity is detected and is calculated using normalization method: chromatographic column: Lux
Cellulose-1 chiral column (4.6mm × 250mm, 5 μm)；Mobile phase: n-hexane-ethyl alcohol (volume ratio 85:15)；Flow velocity:
0.8mL/min；Detection wavelength: 230nm；Column temperature: 30 DEG C.
Embodiment 1
Into 100ml reaction flask, (S) -1-Boc-3- hydroxy piperidine (5.0g, 24.9mmol) and pyridine 20ml, ice is added
Bath is cooled to 5 DEG C or so, and paratoluensulfonyl chloride (5.2g, 27.4mmol) is added in four batches, is stirred overnight at room temperature.Add in reaction solution
Enter ethyl acetate, organic phase washed with water, dilute hydrochloric acid (3M), brine It are concentrated under reduced pressure, and petroleum ether is added in residue
20ml stirs 2.0h, and filtering, petroleum ether, 60 DEG C dry, and obtain white crystal product (S) -1- t-butoxycarbonyl-piperidin -3-
Base-4- methyl-1-benzene sulfonate (8.5g), yield 96%, specific rotatory power: [α]20 D=-24.6 ° (c=1.0, EtOH).
Embodiment 2
Into 100ml reaction flask, be added (S) -1-Boc-3- hydroxy piperidine (5.0g, 24.9mmol), triethylamine (5.0g,
49.5mmol) and methylene chloride 50ml, ice bath is cooled to 5 DEG C or so, be added dropwise into reaction solution mesyl chloride (3.15g,
27.4mmol), it is stirred overnight at room temperature.Organic phase brine It is concentrated under reduced pressure, and petroleum ether 20ml, stirring is added in residue
2.0h, filtering, petroleum ether, 60 DEG C of drying obtain white crystal product (S) -1- t-butoxycarbonyl-piperidin -3- base-methanesulfonic acid
Ester (6.4g), yield 92%, specific rotatory power: [α]20 D=-16.3 ° (c=1.0, EtOH).
Embodiment 3
Into 100ml reaction flask, (S) -1-Boc-3- hydroxy piperidine (5.0g, 24.9mmol), diisopropylethylamine is added
(6.4g, 49.5mmol) and ethyl acetate 50ml, ice bath are cooled to 5 DEG C or so, into reaction solution be added dropwise mesyl chloride (3.15g,
27.4mmol), it is stirred overnight at room temperature.Organic phase brine It is concentrated under reduced pressure, and petroleum ether 20ml, stirring is added in residue
2.0h, filtering, petroleum ether, 60 DEG C of drying obtain white crystal product (S) -1- t-butoxycarbonyl-piperidin -3- base-methanesulfonic acid
Ester (6.6g), 95% specific rotatory power of yield: [α]20 D=-16.4 ° (c=1.0, EtOH).
Embodiment 4
It into 100ml reaction flask, sequentially adds 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-1-benzene sulfonic acid
Ester (7.3g, 20.6mmol) is stirred to react 8.0h in 90 DEG C.Water 200ml is added dropwise into reaction solution, stirs 2.0h, is precipitated yellowish
Color solid, filtering, obtains 4 crude product of midbody compound (5.7g), through re crystallization from toluene, obtains white solid (5.2g), yield 65%,
Chiral HPLC purity 96.3% (S- content of isomer 1.4%), specific rotatory power: [α]20 D=-18.5 ° (c=1.0, EtOH)
Embodiment 5
It into 100ml reaction flask, sequentially adds 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-1-benzene sulfonic acid
Ester (7.3g, 20.6mmol) is stirred to react 6.0h in 100 DEG C.Water 200ml is added dropwise into reaction solution, stirs 2.0h, is precipitated yellowish
Color solid, filtering, obtains 4 crude product of midbody compound (6.1g), through re-crystallizing in ethyl acetate, obtains white solid (5.5g), yield
69%, chiral HPLC purity 97.5% (S- content of isomer 1.2%).Specific rotatory power: [α]20 D=-18.6 ° (c=1.0,
EtOH)。
Embodiment 6
It into 100ml reaction flask, sequentially adds 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-1-benzene sulfonic acid
Ester (7.3g, 20.6mmol) is stirred to react 24.0h in 120 DEG C.Water 200ml is added dropwise into reaction solution, stirs 2.0h, is precipitated light
Yellow solid, filtering, obtains 4 crude product of midbody compound (5.4g), through re crystallization from toluene, obtains white solid (5.0g), yield
62%, chiral HPLC purity 96.4% (S- content of isomer 1.5%).Specific rotatory power: [α]20 D=-18.3 ° (c=1.0,
EtOH)。
Embodiment 7
It into 100ml reaction flask, sequentially adds 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-1-benzene sulfonic acid
Ester (7.3g, 20.6mmol) is stirred to react 4.0h in 160 DEG C.Water 200ml is added dropwise into reaction solution, stirs 2.0h, is precipitated yellowish
Color solid, filtering, obtains 4 crude product of midbody compound (5.5g), through re crystallization from toluene, obtains white solid (5.1g), yield 64%,
Chiral HPLC purity 97.5% (S- content of isomer 1.2%).Specific rotatory power: [α]20 D=-18.5 ° (c=1.0, EtOH).
Embodiment 8
It into 100ml reaction flask, sequentially adds 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-1-benzene sulfonic acid
Ester (7.3g, 20.6mmol) is stirred to react 24.0h in 85 DEG C.Water 200ml is added dropwise into reaction solution, stirs 2.0h, is precipitated yellowish
Color solid, filtering, obtains 4 crude product of midbody compound (5.2g), through re crystallization from toluene, obtains white solid (4.7g), yield 59%,
Chiral HPLC purity 97.5% (S- content of isomer 1.6%).Specific rotatory power: [α]20 D=-18.2 ° (c=1.0, EtOH).
Embodiment 9
It into 100ml reaction flask, sequentially adds 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-1-benzene sulfonic acid
Ester (7.3g, 20.6mmol) is stirred to react 48.0h in 50 DEG C.Water 200ml is added dropwise into reaction solution, stirs 2.0h, is precipitated yellowish
Color solid, filtering, obtains 4 crude product of midbody compound (4.2g), through re-crystallizing in ethyl acetate, obtains white solid (3.8g), yield
47%, chiral HPLC purity 97.3% (S- content of isomer 2.0%).Specific rotatory power: [α]20 D=-17.5 ° (c=1.0,
EtOH)。
Embodiment 10
Into 100ml reaction flask, iodo- 1H- pyrazoles [3, the 4-d] pyrimidine -4- amine (4.3g, 16.5mmol) of 3- is sequentially added,
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-1-benzene sulfonate (7.3g, 20.6mmol), is stirred to react 6.0h in 120 DEG C.Water is added dropwise into reaction solution
200ml stirs 2.0h, faint yellow solid is precipitated, filtering, obtaining intermediate (R) -1- tertbutyloxycarbonyl -3-, (4- amino -3- is iodo-
1H- pyrazolo [3,4-d] pyrimidine -1- base) piperidines crude product (5.4g) through re crystallization from toluene obtains faint yellow solid (4.9g), yield
67%, chiral HPLC purity 97.6% (S- content of isomer 1.2%).Specific rotatory power: [α]20 D=-26.5 ° (c=1.0,
EtOH)。
Embodiment 11
Into 100ml reaction flask, bromo- 1H- pyrazoles [3, the 4-d] pyrimidine -4- amine (3.5g, 16.5mmol) of 3- is sequentially added,
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-1-benzene sulfonate (7.3g, 20.6mmol), is stirred to react 8.0h in 120 DEG C.Water is added dropwise into reaction solution
200ml stirs 2.0h, faint yellow solid is precipitated, filtering, obtaining intermediate (R) -1- tertbutyloxycarbonyl -3-, (4- amino -3- is bromo-
1H- pyrazolo [3,4-d] pyrimidine -1- base) piperidines crude product (4.8g) through re-crystallizing in ethyl acetate obtains faint yellow solid (4.3g),
Yield 65%, chiral 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
It into 100ml reaction flask, sequentially adds intermediate 3 (5.0g, 16.5mmol), DMF (50ml) and cesium carbonate
(16.1g, 49.5mmol), 40 DEG C of stirrings for 24 hours, add (S)-1- t-butoxycarbonyl-piperidin-3- base-4- methyl-1-benzene sulfonic acid
Ester (7.3g, 20.6mmol) is stirred to react 6.0h in 100 DEG C.Water 200ml is added dropwise into reaction solution, stirs 2.0h, is precipitated yellowish
Color solid, filtering, obtains 4 crude product of midbody compound (3.4g), through re-crystallizing in ethyl acetate, obtains white solid (3.1g), yield
38%, chiral HPLC purity 97.4% (S- content of isomer 1.8%).Specific rotatory power: [α]20 D=-17.7 ° (c=1.0,
EtOH)。
Claims (9)
1. a kind of preparation method for replacing Buddhist nun's intermediate according to Shandong as shown in Equation 4, which is characterized in that it includes the following steps: organic
In solvent, under the action of acid binding agent, it is anti-that compound as shown in Equation 2 and compound as shown in Equation 3 are subjected to nucleophilic displacement of fluorine
It answers, is made as shown in Equation 4 and replaces Buddhist nun's intermediate according to Shandong；The acid binding agent is in sodium carbonate, potassium carbonate and sodium hydride
It is one or more；
Wherein, the Y is C1~C6Alkyl, phenyl or " C1~C6Alkyl-substituted phenyl "；The Z is halogen or 4- benzene
Oxygroup-phenyl；
The organic solvent is one of N,N-dimethylformamide, dimethyl sulfoxide and acetonitrile or a variety of；
The molar ratio of the compound as shown in Equation 3 and the acid binding agent is 1:1~1:5；
The temperature of the nucleophilic substitution is 85 DEG C~160 DEG C.
2. the preparation method as shown in Equation 4 for replacing Buddhist nun's intermediate according to Shandong as described in claim 1, which is characterized in that described
C1~C6Alkyl is C1~C3Alkyl；
And/or the C1~C6C described in alkyl-substituted phenyl1~C6Alkyl is C1~C3Alkyl；
And/or the halogen is fluorine, chlorine, bromine or iodine；
And/or the volume mass ratio of the organic solvent and the compound as shown in Equation 3 is 5 mls/g~100
Ml/g.
3. the preparation method as shown in Equation 4 for replacing Buddhist nun's intermediate according to Shandong as described in claim 2, which is characterized in that described
C1~C3Alkyl is methyl；
And/or the halogen is iodine；
And/or the volume mass ratio of the organic solvent and the compound as shown in Equation 3 is 10 mls/g~50
Ml/g.
4. the preparation method as shown in Equation 4 for replacing Buddhist nun's intermediate according to Shandong as described in claim 1, which is characterized in that described
Nucleophilic substitution in, the molar ratio of the compound as shown in Equation 3 and the compound as shown in Equation 2 is 1:
1~1:4.
5. the preparation method as shown in Equation 4 for replacing Buddhist nun's intermediate according to Shandong as described in claim 4, which is characterized in that described
Nucleophilic substitution in, the molar ratio of the compound as shown in Equation 3 and the compound as shown in Equation 2 is 1:
1~1:2；
And/or in the nucleophilic substitution, the molar ratio of the compound as shown in Equation 3 and the acid binding agent
For 1:2~1:4.
6. the preparation method as shown in Equation 4 for replacing Buddhist nun's intermediate according to Shandong as described in claim 1, which is characterized in that
The time of the nucleophilic substitution is 4~24 hours；
And/or the preparation method that Buddhist nun's intermediate is replaced according to Shandong as shown in Equation 4, it is being tied in the nucleophilic substitution
Shu Hou further comprises the operation of post-processing；The post-processing are as follows: after reaction mix reaction system with water, mistake
Filter；
And/or the described preparation method that Buddhist nun's intermediate is replaced according to Shandong as shown in Equation 4, Buddhist nun is replaced according to Shandong being made as shown in Equation 4
After intermediate, further include the steps that purifying products.
7. the preparation method as shown in Equation 4 for replacing Buddhist nun's intermediate according to Shandong as described in claim 6, which is characterized in that described
Nucleophilic substitution temperature be 100 DEG C~120 DEG C；
And/or it is described it is as shown in Equation 4 according to Shandong in the preparation method of Buddhist nun's intermediate, the nucleophilic substitution when
Between be 6~12 hours；
And/or the step of described purifying products is recrystallization.
8. the preparation method as shown in Equation 4 for replacing Buddhist nun's intermediate according to Shandong as described in claim 1, which is characterized in that described
The preparation method that Buddhist nun's intermediate is replaced according to Shandong as shown in Equation 4, also comprise the following steps: by the chemical combination as shown in Equation 2
Object is added in the mixture of the compound as shown in Equation 3, the acid binding agent and the organic solvent, carries out institute
The nucleophilic substitution stated.
9. the preparation method as shown in Equation 4 for replacing Buddhist nun's intermediate according to Shandong as described in claim 8, which is characterized in that described
Compound as shown in Equation 3, the acid binding agent and the organic solvent the temperature of mixture be 30 DEG C~50 DEG C.
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