CN109206426A - The preparation method of Pyrazolopyrimidines - Google Patents

The preparation method of Pyrazolopyrimidines Download PDF

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CN109206426A
CN109206426A CN201710548070.4A CN201710548070A CN109206426A CN 109206426 A CN109206426 A CN 109206426A CN 201710548070 A CN201710548070 A CN 201710548070A CN 109206426 A CN109206426 A CN 109206426A
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compound
equation
alkali
amidation
sodium
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刘学军
李云飞
程吉
李春丽
洪辉意
陈晓冬
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Shanghai Double Star Thai Pharmaceutical Technology Co Ltd
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Shanghai Double Star Thai Pharmaceutical Technology Co Ltd
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04Ortho-condensed systems

Abstract

The invention discloses a kind of preparation methods of Pyrazolopyrimidines.The preparation method of Pyrazolopyrimidines provided by the invention, comprises the steps of, in organic solvent, under the action of alkali and water, compound as shown in Equation 1 and compound as shown in Equation 2 are carried out amidation process as follows;The alkali is selected from one of phosphoric acid class sylvite, phosphoric acid class sodium salt, sodium acetate, potassium acetate, sodium citrate and potassium citrate or a variety of.This method is easily operated, reaction condition is mild, purity is good, high income, is more suitable for industrialized production.

Description

The preparation method of Pyrazolopyrimidines
Technical field
The present invention relates to the preparation methods of Pyrazolopyrimidines.
Background technique
Buddhist nun, the entitled Ibrutinib of English, chemical name: 1- [(3R) -3- [4- amino -3- (4- phenoxy group benzene are replaced according to Shandong Base) -1H- pyrazolo [3,4-d] pyrimidine -1- base] -1- piperidyl] -2- propylene -1- ketone.According to Shandong for Buddhist nun by the U.S. Pharmacyclics and Johnson & Johnson of the U.S. (Johnson&Johnson) research and development, are obtained on November 13rd, 2013 in U.S. FDA approval City obtains EMA approval listing, by Pharmacyclics in U.S.'s list marketing, by Johnson & Johnson in Europe on October 21st, 2014 later Continent list marketing, trade name are Imbruvica.
One kind is disclosed in patent application WO2016115356 according to Shandong for Buddhist nun and its intermediate 1- [(3R) -3- [4- amino - 3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine -1- base] -1- piperidyl] -3- chloropropane -1- ketone preparation side Method, as shown in reaction equation 1:
Reaction equation 1:
This method uses 3- chlorpromazine chloride as amidation reagent, with inorganic base sodium bicarbonate (NaHCO3) aqueous solution conduct Acid binding agent obtains intermediate without isolation, and elimination reaction occurs in the presence of alkali and generates target compound according to Shandong for Buddhist nun.This side The dosage of method 3- chlorpromazine chloride has larger impact to impurity.In this method, 3- chlorpromazine chloride needs be added portionwise, first plus Enter 0.9 equivalent 3- chlorpromazine chloride, the 3- chlorpromazine chloride that result adds calculation amount is then controlled in.If being added at one time excess 3- chlorpromazine chloride may be such that pyrilamine amidation impurity content increases, and be difficult to remove.Impurity is difficult to control, so that producing Quality is controlled risk increase, and increased production cost, is unsuitable for industrialized production.In this method, first step purity 98%, yield It is 87%, second step yield 80%, purity does not refer to.
One kind is disclosed in patent application WO2016170545 according to Shandong for Buddhist nun and its intermediate 1- [(3R) -3- [4- amino - 3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine -1- base] -1- piperidyl] -3- chloropropane -1- ketone preparation side Method, as shown in reaction equation 2:
Reaction equation 2:
This method uses 3- chlorpromazine chloride as amidation reagent, with organic bases triethylamine (TEA) or diisopropyl second Base amine (DIPEA) is used as acid binding agent, and intermediate carries out crystallization purifying with petroleum ether;Amidation intermediate continues in the presence of alkali Elimination reaction occurs and generates target compound according to Shandong for Buddhist nun.The method amidation step reaction temperature is -40~-45 DEG C, to setting It is standby more demanding, increase production cost and security risk.In addition, amidation intermediate needs to carry out Crystallization Separation, but separate Purity is unsatisfactory, not only increases additional technological operation, also reduces yield, is unsuitable for industrialized production.In this method, First step yield 72%, purity 91%.Second step yield 32%, purity 99%.
Therefore, how to provide it is a kind of it is at low cost, easily operated, reaction condition is mild, purity is good, high income is more suitable for work The preparation method that Buddhist nun and its intermediate are replaced according to Shandong that industry metaplasia produces, is the research and development difficult point of this field.
Summary of the invention
The technical problem to be solved by the present invention is to be prepared in the prior art according to Shandong to overcome for Buddhist nun and its intermediate process Middle amidation process requires harshness to condition, and operation difficulty is big, the low problem of yield, to provide a kind of Pyrazolopyrimidines type The preparation method of compound.This method is easily operated, reaction condition is mild, purity is good, high income, is more suitable for industrialized production.
The present invention mainly solves above-mentioned technical problem by the following technical programs.
The present invention provides a kind of preparation method of compound as shown in Equation 3, it includes following steps, in organic solvent, Under the action of alkali and water, compound as shown in Equation 1 and compound as shown in Equation 2 are subjected to amidation process as follows, ?;
R1、R2、R3、R4、R5、R6、R7、R8And R9It is separately H, C1-3Alkyl or C1-3Alkoxy;
X1And X2It is each independently halogen, such as fluorine, chlorine, bromine or iodine;The X1And X2It may be the same or different;
The alkali is selected from phosphoric acid class sylvite (for example, one of potassium dihydrogen phosphate, dipotassium hydrogen phosphate and potassium phosphate or more Kind), phosphoric acid class sodium salt (for example, one of sodium dihydrogen phosphate, disodium hydrogen phosphate and sodium phosphate or a variety of), sodium acetate, acetic acid One of potassium, sodium citrate and potassium citrate are a variety of.
In the amidation process, the mole dosage ratio of the compound as shown in Equation 2 and the compound as shown in Equation 1 It can be the conventional ratio of such reaction of this field, such as 1:1~3:1, then such as 1.2:1.
In the amidation process, the organic solvent can be the conventional organic solvent of this field, such as ether solvent, institute Stating ether solvent can be selected from one of tetrahydrofuran, 2- methyltetrahydrofuran, methyl tertiary butyl ether(MTBE) and methyl phenyl ethers anisole or a variety of.
In the amidation process, the dosage of the solvent can be the conventional amount used of such reaction of this field, such as described The molal volume ratio of compound as shown in Equation 1 and the solvent can be 0.13mol/L~0.39mol/L, such as 0.27mol/L.
In the amidation process, the molar ratio of the alkali and the compound as shown in Equation 1 can be 0.5:1~4:1, example Such as, 1:1~3:1.
In the amidation process, the molar ratio of the water and the compound as shown in Equation 1 can be 0.5:1~3:1, example Such as 2:1.
The temperature of the amidation process can be -20~30 DEG C, such as 5~15 DEG C.
In the present invention, the temperature of the reaction refers to interior temperature, reacting liquid temperature when the interior temperature refers to reaction.
The time of the amidation process can be detected according to HPLC judges whether reaction is completed.
The amidation process, can include the following steps:, will be described such as formula 2 under the action of alkali and water in organic solvent Compound represented is added in the compound as shown in Equation 1, carries out the amidation process;The addition Mode be for example added dropwise;
Alternatively, the compound as shown in Equation 2 is added to the alkali, the compound as shown in formula and described organic In the mixed solution of solvent, the amidation process is carried out;The mode of the addition is for example added dropwise;
The preparation method of the compound as shown in Equation 3, can include the following steps: by the alkali and water be added to it is described such as Compound shown in formula 1 in the organic solvent, extremely -20~30 DEG C of adjustment temperature, is added dropwise the compound as shown in Equation 2, stirs It mixes.
In the present invention, the temperature of the reaction refers to interior temperature, reacting liquid temperature when the interior temperature refers to reaction.
Wherein, the temperature can also be 5~15 DEG C.
Wherein, the time of the stirring can be 0.5~20 hour, such as 1~2 hour.
The preparation method of the compound as shown in Equation 3 also may include post-processing.
The post-processing can refer to the conventional method and operation of such reaction of this field, such as layering, washing, be concentrated under reduced pressure And/or crystallization.
The conventional wash mode of such reaction of this field can be used in the washing, and 7% sodium bicarbonate aqueous solution can be used As cleaning solution;The dosage of the cleaning solution can be 8 times of the compound quality as shown in Equation 1.
Wirking pressure when pressure when the reduced pressure can be concentrated under reduced pressure for this field, such as -0.08~- 0.1MPa;The temperature when reduced pressure can be 20~30 DEG C;It can be carried out when the reduced pressure repeatedly, such as 4 times;It is described When reduced pressure carries out multiple, ethyl acetate can be used and carry out solvent make-up;
It, can be according to the following steps: the organic phase obtained after the washing is subtracted when the reduced pressure carries out multiple Pressure is concentrated into 1/2 volume, then with ethyl acetate be concentrated under reduced pressure displacement 3 times (dosage of the ethyl acetate added every time with The volume mass ratio of the compound as shown in Equation 1 is 6ml/g, and is concentrated under reduced pressure into 1/2 volume).
2- methyltetrahydrofuran/n-heptane system or ethyl acetate/n-heptane system can be used in the crystallization.
The present invention also provides a kind of preparation methods of compound as shown in Equation 4, and it includes following steps:
(1) in organic solvent, under the action of alkali and water, compound as shown in Equation 1 and compound as shown in Equation 2 are carried out Amidation process as follows;
(2) in solvent, under the action of alkali, compound shown in the formula 3 being prepared in step (1) is subjected to elimination reaction, ?;
Substituent group definition, reaction condition in step (1) is as described in claim any one of 1-6;
R1~R9And the definition of X is as described in claims 1 or 2.
In the step (2), the elimination reaction can refer to the operation and method of such reaction of this field, for example, this Invention uses following operation and method:
The common alkali that such in this field reacts, such as DBU and/or triethylamine can be used in alkali described in step (2).
Solvent described in step (2) can be the Conventional solvents in this field, such as ethyl acetate and/or isopropyl acetate; The molal volume ratio of solvent described in the compound as shown in Equation 1 and step (2) can be 0.13mol/L~0.39mol/L.
Wherein, the molar ratio of 3 compound of alkali described in step (2) and the formula can refer to the routine of such reaction of this field Ratio, such as 1:1~10:1, then such as 2.5:1.
Wherein, the elimination reaction temperature can be -10~30 DEG C, such as 12~14 DEG C.
Wherein, the elimination reaction time can detect whether reaction is completed according to HPLC, such as the reaction time is 1~25 small When, then such as 7~8 hours.
Wherein, sodium trifluoroacetate can be also added in the elimination reaction, the compound 1 and the sodium trifluoroacetate rub Your amount ratio can be 1:1~3:1, such as 2:1.The elimination reaction also may include post-processing.
It is described post-processing can refer to this field such reaction routine operation and method, such as comprising acidification, liquid separation, wash It one of washs, be concentrated under reduced pressure and crystallize or is a variety of.
It can be used when the acidification 5% hydrochloric acid (mass concentration), the compound as shown in Equation 1 and 5% hydrochloric acid Molal volume ratio can be 1:1~1:3, such as 1:2.
The liquid separation can refer to the mode of operation of the conventional liquid separation of this field, obtain organic phase and water phase.
The water phase obtained after liquid separation can also be extracted after the liquid separation, ethyl acetate can be used as extraction in the extraction Take agent, the volume mass ratio of the extractant and the compound as shown in Equation 1 can be 3~6mL/g, such as 5mL/g.
It is described washing can be used 13% aqueous citric acid solution wash repeatedly (such as 3 times), every time washing when described in 13% lemon The volume mass ratio of lemon aqueous acid and the compound as shown in Equation 1 can be 3~6mL/g, such as 5mL/g;Then with 9% carbon Acid sodium aqueous solution washing and purifying water washing, the volume mass of 9% aqueous sodium carbonate and the compound as shown in Equation 1 Than that can be 3~5mL/g, such as 4mL/g;The volume mass ratio of the purified water and the compound as shown in Equation 1 can for 3~ 5mL/g, such as 4mL/g;Organic phase is obtained, is then concentrated under reduced pressure into 1/2 volume at 15~25 DEG C.
It is described to crystallize the crystallization mode that can refer to this field compound, it is crystallized using normal heptane, the normal heptane Volume mass ratio with the compound as shown in Equation 1 can be 7~12mL/g, such as 9mL/g.
It also may include washing and/or drying after the crystallization;The washing and dry method and operation can refer to this Routine operation in field.
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: the present invention is walked using inorganic base unlike the prior art as amidation Rapid acid binding agent.Impurity is easier to control in reaction, improves to the tolerance of the additional amount of disposable 3- chlorpromazine chloride, it is not easy to produce Sheng Yilu replaces the related substance of Buddhist nun;Reaction condition is mild, stable yield.Compared to method reported in the literature, this method does not increase volume Outer step, and risk is smaller, production cost reduces, and is suitable for industrialized production, there is biggish application value.
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.
Embodiment 1:1- [(3R) -3- [4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine -1- Base] -1- piperidyl] -3- chloropropane -1- ketone (compound 3) preparation
Compound as shown in Equation 1 (1.0g), 2- methyltetrahydrofuran (8.2g) are added in the Jacketed bottle of 100ml, nitrogen Potassium dihydrogen phosphate (1.06g) and water (2g) is added in protection, adjusts temperature to 5~15 DEG C of interior temperature.3- chlorpromazine chloride is slowly added dropwise (0.39g) is finished and is continued stirring 1 hour.Stratification, sodium bicarbonate aqueous solution (8.0g) washing of organic phase 7%, organic phase It is concentrated under reduced pressure into 4~5ml at 20~25 DEG C, is added ethyl acetate (5g), is concentrated under reduced pressure into 4~5ml, is repeated two more times and adds second Acetoacetic ester and the operation being concentrated.It is added ethyl acetate (7g), obtains the ethyl acetate solution of the compound 3 containing 1.2g (12.5g), deepfreeze (0~5 DEG C).The yield of compound 3 is 95%, and purity 99% is free of related substance (R)-N- (1- (1- acryloylpiperidine -3- base) -3- (4- Phenoxyphenyl) -1H- pyrazoles [3.4-d] pyrimidine-4-yl) acrylamide.
Embodiment 2:1- [(3R) -3- [4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine -1- Base] -1- piperidyl] -2- propylene -1- ketone (compound 4) preparation
The ethyl acetate solution (12.5g) of compound 3 in embodiment 1 is added in 100ml Jacketed bottle, trifluoro second is added Sour sodium (0.18g).12~14 DEG C of temperature in control, is added dropwise 1,8- diazabicylo, 11 carbon -7- alkene (0.98g), it is small to be stirred to react 8 When.10~20 DEG C of temperature in control, is added dropwise 5% dilute hydrochloric acid (1.9g), and stirring layering, water phase is merged with ethyl acetate (4g) extraction Organic phase, three times (each 5g) with the washing of 13% aqueous citric acid solution, then with 9% aqueous sodium carbonate (4g) and purified water (4g) Washing is concentrated under reduced pressure into 6ml at 15~25 DEG C, controls interior warm 10~15 DEG C of dropwise addition normal heptanes (6g), and stirring is cooled to 0~5 DEG C, Filtering washs filter cake with ethyl acetate/normal heptane (1/1,1.5g), and wet product is dried under reduced pressure 20 hours in 35~45 DEG C, obtains 0.87g white solid, i.e. compound 4, this step yield 79%, purity 99.5%.
Embodiment 1-2, by compound prepare compound 4 as shown in Equation 1, two steps add up to yield to be 75%.
Embodiment 3:1- [(3R) -3- [4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine -1- Base] -1- piperidyl] -3- chloropropane -1- ketone (compound 3) preparation
Compound as shown in Equation 1 (70.0g), 2- methyltetrahydrofuran (574g) are added in the Jacketed bottle of 3000ml, nitrogen Potassium dihydrogen phosphate aqueous solution 74.2g, water 140g is added in gas shielded, adjusts temperature to 5~15 DEG C of interior temperature.3- chlorine third is slowly added dropwise Acyl chlorides (27.3) finishes and continues stirring 1 hour.Stratification, sodium bicarbonate aqueous solution (560.0g) washing of organic phase 7%, Organic phase is concentrated under reduced pressure into 280~350ml at 20~25 DEG C, is added ethyl acetate (350.0g), it is concentrated under reduced pressure into 280~ 350ml is repeated two more times the operation adding ethyl acetate and being concentrated.The quality of obtained compound 3 is 82.9g, and acetic acid is added Ethyl ester (490.0g) obtains the solution (930.0g) of compound 3, deepfreeze (0~5 DEG C).Yield 96%, purity 99%.No Containing related substance (R)-N- (1- (1- acryloylpiperidine -3- base) -3- (4- Phenoxyphenyl) -1H- pyrazoles [3.4-d] pyrimidine - 4- yl) acrylamide.
Embodiment 4:1- [(3R) -3- [4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine -1- Base] -1- piperidyl] -2- propylene -1- ketone (compound 4) preparation
The ethyl acetate solution (930.0g) of compound 3 in embodiment 3 is added in 100ml Jacketed bottle, trifluoro is added Sodium acetate (12.6g).12~14 DEG C of temperature in control, is added dropwise 1,8- diazabicylo, 11 carbon -7- alkene (69.6g), is stirred to react 8 Hour.Interior 10~20 DEG C of the temperature of control, is added dropwise 5% dilute hydrochloric acid (133g), and stirring layering, water phase is extracted with ethyl acetate (280g), Merge organic phase, three times (each 350g) with the washing of 13% aqueous citric acid solution, then with 9% aqueous sodium carbonate (280g) and pure Change water (280g) washing, 6ml is concentrated under reduced pressure at 15~25 DEG C, controls interior warm 10~15 DEG C of dropwise addition normal heptanes (420g), stirring It is cooled to 0~5 DEG C, filtering washs filter cake with ethyl acetate/normal heptane (1/1,105g), and wet product is dried under reduced pressure in 35~45 DEG C 20 hours, obtain 61.3g white solid, i.e. compound 4, the independent yield 80% of this step, purity 99.5%.Embodiment 3-4, by such as Compound prepare compound 4 shown in formula 1, two step yields 76.8%.
Embodiment 5
Reference implementation example 1 replaces potassium dihydrogen phosphate with sodium citrate, mixing time 1h, the yield of amidation process It is 91%, purity 98.3%.Without related substance (R)-N- (1- (1- acryloylpiperidine -3- base) -3- (4- phenoxy group benzene Base) -1H- pyrazoles [3.4-d] pyrimidine-4-yl) acrylamide.
Embodiment 6
1- [(3R) -3- [4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine -1- base] -1- piperidines Base] -3- chloropropane -1- ketone (compound 3) preparation
Compound as shown in Equation 1 (1.0g), methyl tertiary butyl ether(MTBE) (6.7ml) are added in the Jacketed bottle of 100ml, nitrogen is protected Sodium dihydrogen phosphate (0.20g) and water (6g) is added in shield, adjusts temperature to 5~15 DEG C of interior temperature.3- chlorpromazine chloride is slowly added dropwise (0.325g) is finished and is continued stirring 1 hour.Stratification, sodium bicarbonate aqueous solution (8.0g) washing of organic phase 7% are organic It is mutually concentrated under reduced pressure into 4~5ml at 20~25 DEG C, is added ethyl acetate (5g), is concentrated under reduced pressure into 4~5ml, is repeated two more times and adds Ethyl acetate and the operation being concentrated.It is added ethyl acetate (7g), obtains the ethyl acetate solution of the compound 3 containing 1.2g (12.5g), deepfreeze (0~5 DEG C).The yield of compound 3 is 94%, purity 98%.Without related substance (R)-N- (1- (1- acryloylpiperidine -3- base) -3- (4- Phenoxyphenyl) -1H- pyrazoles [3.4-d] pyrimidine-4-yl) acrylamide.
Embodiment 7
1- [(3R) -3- [4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine -1- base] -1- piperidines Base] -3- chloropropane -1- ketone (compound 3) preparation
Compound as shown in Equation 1 (1.0g), methyl phenyl ethers anisole (19.9ml) are added in the Jacketed bottle of 100ml, nitrogen protection adds Enter sodium acetate 1.41g) and water (1g), temperature is adjusted to 5~15 DEG C of interior temperature.3- chlorpromazine chloride (0.975g) is slowly added dropwise, finishes Continue stirring 1 hour.Stratification, sodium bicarbonate aqueous solution (8.0g) washing of organic phase 7%, organic phase subtract at 20~25 DEG C Pressure is concentrated into 4~5ml, is added ethyl acetate (5g), is concentrated under reduced pressure into 4~5ml, is repeated two more times and adds ethyl acetate and be concentrated Operation.It is added ethyl acetate (7g), obtains the ethyl acetate solution (12.5g) of the compound 3 containing 1.2g, deepfreeze (0 ~5 DEG C).The yield of compound 3 is 94.9%, purity 98.5%.Without related substance (R)-N- (1- (1- acryloyl group piperazine Pyridine -3- base) -3- (4- Phenoxyphenyl) -1H- pyrazoles [3.4-d] pyrimidine-4-yl) acrylamide.
Comparative example 1
Reference implementation example 1, potassium dihydrogen phosphate is replaced with triethylamine, and the yield of mixing time 2h, amidation process are 69%, purity 75.7%.Without related substance (R)-N- (1- (1- acryloylpiperidine -3- base) -3- (4- phenoxy group benzene Base) -1H- pyrazoles [3.4-d] pyrimidine-4-yl) acrylamide.
Comparative example 2
The operation of reference implementation example 1, unlike, potassium dihydrogen phosphate is replaced with saleratus, mixing time 2h, acyl The yield of aminating reaction is 80%, purity 86.4%.Without related substance (R)-N- (1- (1- acryloylpiperidine -3- base) - 3- (4- Phenoxyphenyl) -1H- pyrazoles [3.4-d] pyrimidine-4-yl) acrylamide.
Comparative example 3
The operation of reference implementation example 1, unlike, potassium dihydrogen phosphate is replaced with sodium carbonate, dosage is 1.5 times such as formula The mole dosage of compound shown in 1, mixing time 2h, the yield of amidation process are 89%, purity 95.1%.It does not contain Close substance (R)-N- (1- (1- acryloylpiperidine -3- base) -3- (4- Phenoxyphenyl) -1H- pyrazoles [3.4-d] pyrimidine -4- Base) acrylamide.
Comparative example 4
The operation of reference implementation example 1, unlike, potassium dihydrogen phosphate is replaced with sodium acetate, mixing time 2h, amide The yield for changing reaction is 85%, purity 92.8%.
Comparative example 5
The technical solution recorded in referenced patent WO2016115356 is disposably added dropwise 1.2 in the way of the application and works as In the 3- chlorpromazine chloride of amount, yield and bibliography quite, it can reach 87%, but a small amount of impurity should be easy to appear in the process ((R)-N- (1- (1- acryloylpiperidine -3- base) -3- (4- Phenoxyphenyl) -1H- pyrazoles [3.4-d] pyrimidine-4-yl) propylene Amide), which is not easy to remove, to replace the related substance in Buddhist nun according to Shandong.

Claims (10)

1. a kind of preparation method of compound as shown in Equation 3, which is characterized in that comprise the steps of, in organic solvent, in alkali and Under the action of water, compound as shown in Equation 1 and compound as shown in Equation 2 are subjected to amidation process as follows;
The R1、R2、R3、R4、R5、R6、R7、R8And R9It is separately H, C1-3Alkyl or C1-3Alkoxy;
X1And X2It is each independently halogen, the X1And X2It may be the same or different;
The alkali in phosphoric acid class sylvite, phosphoric acid class sodium salt, sodium acetate, potassium acetate, sodium citrate and potassium citrate one Kind is a variety of.
2. preparation method as described in claim 1, which is characterized in that the phosphoric acid class sylvite is selected from potassium dihydrogen phosphate, phosphoric acid One of hydrogen dipotassium and potassium phosphate are a variety of;And/or the phosphoric acid class sodium salt be selected from sodium dihydrogen phosphate, disodium hydrogen phosphate and One of sodium phosphate is a variety of;And/or the halogen is fluorine, chlorine, bromine or iodine.
3. preparation method as described in claim 1, which is characterized in that the compound as shown in Equation 2 and it is described as shown in Equation 1 The molar ratio of compound is 1:1~3:1, preferably 1.2:1;
And/or the organic solvent is ether solvent, preferably tetrahydrofuran, 2- methyltetrahydrofuran, methyl tertiary butyl ether(MTBE) and benzene One of methyl ether is a variety of;
And/or the molal volume ratio of the compound as shown in Equation 1 and the organic solvent is 0.13mol/L~0.39mol/ L, preferably 0.27mol/L;
The molar ratio of the water and the compound as shown in Equation 1 is 0.5:1~3:1, preferably 2:1;
And/or the molar ratio of the alkali and the compound as shown in Equation 1 is 0.5:1~4:1, preferably 1:1~3:1.
4. preparation method as described in claim 1, which is characterized in that the temperature of the amidation process is -20~30 DEG C, excellent Select 5~15 DEG C.
5. preparation method as described in claim 1, which is characterized in that comprise the steps of, in organic solvent, in alkali and water Under effect, the compound as shown in Equation 2 is added in the compound as shown in Equation 1, carries out the amidation Reaction;The mode of the addition is preferably added dropwise;
Alternatively, the compound as shown in Equation 2 is added to the alkali, the compound as shown in formula and the organic solvent Mixed solution in, carry out the amidation process;The mode of the addition is preferably added dropwise.
6. preparation method as described in any one in claim 1-5, which is characterized in that by compound as shown in Equation 1 and such as 2 institute of formula When showing that compound carries out amidation process, the alkali and water are added to the compound as shown in Equation 1, the organic solvent In, the compound as shown in Equation 2, stirring is added dropwise to -20~30 DEG C in adjustment temperature;Preferably 5~15 DEG C of the temperature.
7. a kind of preparation method of compound as shown in Equation 4, which is characterized in that comprise the steps of:
(1) in organic solvent, under the action of alkali and water, compound as shown in Equation 1 and compound as shown in Equation 2 are carried out as follows Shown in amidation process;
(2) in solvent, under the action of alkali, compound shown in the formula 3 being prepared in step (1) is subjected to elimination reaction;
Substituent group definition, reaction condition in step (1) is as described in claim any one of 1-6;
R1~R9And the definition of X is as described in claims 1 or 2.
8. preparation method as claimed in claim 7, which is characterized in that
Alkali described in step (2) is DBU and/or triethylamine;
And/or solvent described in step (2) is ethyl acetate and/or isopropyl acetate;
And/or the molal volume ratio of solvent described in the compound as shown in Equation 1 and step (2) be 0.13mol/L~ 0.39mol/L;
And/or the molar ratio of 3 compound of alkali described in step (2) and the formula is 1:1~10:1, preferably 2.5:1;
And/or the elimination reaction temperature is -10~30 DEG C, preferably 12~14 DEG C;
And/or the elimination reaction time preferably 1~25 hour, further preferred 7~8 hours.
9. preparation method as claimed in claim 7, which is characterized in that be additionally added sodium trifluoroacetate in the elimination reaction.
10. preparation method as claimed in claim 9, which is characterized in that mole of the compound 1 and the sodium trifluoroacetate Amount ratio is 1:1~3:1, preferably 2:1.
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104945404A (en) * 2014-06-25 2015-09-30 广东东阳光药业有限公司 Method for preparing N-propylene carbonyl piperidine derivative
WO2016115356A1 (en) * 2015-01-14 2016-07-21 Pharmacyclics Llc Synthesis of a bruton's tyrosine kinase inhibitor
CN105859721A (en) * 2015-01-22 2016-08-17 浙江京新药业股份有限公司 Method for preparing ibrutinib
WO2016132383A1 (en) * 2015-02-18 2016-08-25 Mylan Laboratories Limited Process for the preparation of ibrutinib
CN105985344A (en) * 2015-02-12 2016-10-05 上海昶朗医药科技有限公司 Synthetic method for ibrutinib and intermediate of ibrutinib
WO2016170545A1 (en) * 2015-04-22 2016-10-27 Msn Laboratories Private Limited Process for the preparation of 1-[(3r)-3-[4-amino-3-(4-phenoxyphenvl)-1h- pvrazolo[3,4-d]pyriniidin-1-y1]-1-piperidinvl]-2-propen-1-one and its polymorphs thereof

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104945404A (en) * 2014-06-25 2015-09-30 广东东阳光药业有限公司 Method for preparing N-propylene carbonyl piperidine derivative
WO2016115356A1 (en) * 2015-01-14 2016-07-21 Pharmacyclics Llc Synthesis of a bruton's tyrosine kinase inhibitor
CN105859721A (en) * 2015-01-22 2016-08-17 浙江京新药业股份有限公司 Method for preparing ibrutinib
CN105985344A (en) * 2015-02-12 2016-10-05 上海昶朗医药科技有限公司 Synthetic method for ibrutinib and intermediate of ibrutinib
WO2016132383A1 (en) * 2015-02-18 2016-08-25 Mylan Laboratories Limited Process for the preparation of ibrutinib
WO2016170545A1 (en) * 2015-04-22 2016-10-27 Msn Laboratories Private Limited Process for the preparation of 1-[(3r)-3-[4-amino-3-(4-phenoxyphenvl)-1h- pvrazolo[3,4-d]pyriniidin-1-y1]-1-piperidinvl]-2-propen-1-one and its polymorphs thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
丁永正等: "依鲁替尼合成路线图解", 《中国药物化学杂志》 *

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