CN107814804A - The preparation method of Buddhist nun is replaced according to Shandong - Google Patents

The preparation method of Buddhist nun is replaced according to Shandong Download PDF

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Publication number
CN107814804A
CN107814804A CN201711024520.6A CN201711024520A CN107814804A CN 107814804 A CN107814804 A CN 107814804A CN 201711024520 A CN201711024520 A CN 201711024520A CN 107814804 A CN107814804 A CN 107814804A
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compound
solvent
alkali
shandong
buddhist nun
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王勇
卢江
俞金泉
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Ke Ruite Bio Tech Ltd Guangzhou
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Ke Ruite Bio Tech Ltd Guangzhou
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

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  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to the preparation method that Buddhist nun is replaced according to Shandong.Its step is compound A ((R) 3 (4 Phenoxyphenyl) 1 (base of piperidines 3) 1H pyrazolos [3; 4 D] 4 amine of pyrimidine) with compound C intermediate B is obtained by acylation reaction, finally obtain replacing Buddhist nun according to Shandong by elimination reaction；Preparation method reaction condition provided by the invention is gentle, and impurity is few, high income, easily amplification, suitable for industrialized production.

Description

The preparation method of Buddhist nun is replaced according to Shandong
Technical field
The present invention relates to technical field of medicine synthesis, is related to a kind of novel synthesis that Buddhist nun is replaced according to Shandong.
Background technology
It is a kind of small molecule BTK inhibitor to replace Buddhist nun (Imbruvica, Ibrutinib) according to Shandong, can be with BTK activated centres Cysteine residues covalent bond, so as to suppress its activity.BTK full name Bruton'styrosinekinase, believe in BCR Signal, migration, chemotactic, the adhesion of mediate B cell are transmitted in number path, cytokine receptor signal path.Preclinical study is demonstrate,proved It is bright, propagation, the existence of Malignant B cell can be suppressed for Buddhist nun according to Shandong.
The medicine obtains FDA approvals in November, 2013, previously receives the set of other drugs treatment at least once for treating Cell lymphoma (MCL) patient.In recent years, its granted indication scope constantly expands, including：Chronic lymphocytic leukemia (CLL)/SLL (SLL), chronic lymphocytic leukemia (CLL)/primary lymphedema of chromosome 17P missings are thin Born of the same parents' property lymthoma (SLL), Waldenstrom macroglobulinemias, marginal zone lymphoma (Marginal zone lymphoma, MZL)。
It is shown below according to Shandong for the structure of Buddhist nun
At present, have according to Shandong for the synthetic method patent of Buddhist nun：Patent CN101674834, patent CN101610676, patent CN102746305, WO2014022390 and WO2012158795；Patent CN105859728；Patent CN104557946.Its is main Synthetic method is as follows：
Patent CN101674834, patent CN101610676, patent CN102746305, WO2014022390 and WO2012158795 reports method 1 synthetic route, and compound D and F react through Mitsunobu, de- Boc protections Compound A ((R) -3- (4- Phenoxyphenyls) -1- (piperidines -3- bases) -1H- pyrazolos [3,4-D] pyrimidine -4- amine), then same propylene Acyl chloride reaction obtains replacing Buddhist nun according to Shandong, and double acrylated impurity and polymerization impurity are more during this method synthesis replaces Buddhist nun according to Shandong, It is not easy to remove, while propionyl chloride is costly, easily polymerization is not easy to maintain, is not suitable for amplification production.Patent CN105859728 is reported Road method 2 synthetic route, last intermediate A and acrylic acid obtain replacing Buddhist nun according to Shandong through condensation reaction, but are also deposited in reacting More in side reaction, impurity is not easy to remove, and acrylic acid equally easily polymerize not easy to maintain, the unsuitable amplification production of the route.Patent CN104557946 reports method 3 synthetic route, and first acryloyl group is connected on piperidine ring and obtains intermediate E, finally React to obtain by Mitsunobu and replace Buddhist nun according to Shandong, this method synthetic route is shorter, and is finally reacted using Mitsunobu, secondary Product is more, and caused genotoxicity impurity is not easy to remove, and is not suitable for the production of pharmaceutical industries metaplasia.
The content of the invention
It is an object of the invention to in the prior art the defects of, there is provided a kind of new preparation method that Buddhist nun is replaced according to Shandong.
The present invention also aims to provide a kind of compound for being used for synthesis according to Shandong for Buddhist nun.
The above-mentioned purpose of the present invention is realized by following technological means：
The invention provides Buddhist nun is replaced according to Shandong, its preparation method is compound A ((R) -3- (4- Phenoxyphenyls) -1- (piperazines Pyridine -3- bases) -1H- pyrazolos [3,4-D] pyrimidine -4- amine) with compound C occur acylation reaction obtain intermediate B, then pass through Elimination reaction obtains replacing Buddhist nun according to Shandong, and reaction equation is as follows：
Wherein, R, X separately one kind in leaving group.As long as R, X is leaving group, according to ability The common knowledge in domain, acylated and elimination reaction can occur, you can realize the purpose of the present invention.Specifically, described R, X are independent The one kind of ground in halogen, bound phosphate groups, sulfate group, sulfonate ester group；As described in preferred embodiment R, X is independently selected from Cl, Br, I, F, methanesulfonic acid ester group (OMs), p-methyl benzenesulfonic acid ester group (OTs) and trifluoromethanesulfonic acid ester group (OTf) one kind in.As exemplary embodiment, described R and X are separately Cl or Br, now, compound C For chlorpromazine chloride, bromopropionyl bromide, chlorine propionyl bromide or bromo propionyl chloro.
Specifically, preparation method of the invention comprises the following steps：
(1) acylation reaction：Compound A：(R) -3- (4- Phenoxyphenyls) -1- (piperidines -3- bases) -1H- pyrazolos [3, 4-D] pyrimidine -4- amine and compound C, under the protection of inert gas, in the presence of a base, reaction obtains intermediate B；
Wherein, in step (1), compound A and compound C rate of charge is 4:1-1:5.As preferred embodiment, Rate of charge is 0.8:1-1:0.8.
Wherein, in step (1), compound C is to be mixed by way of disposably adding or being added dropwise with compound A, preferably Ground, mixed by being added dropwise with compound A, with the speed of control reaction.
Wherein, in step (1), described alkali is not particularly limited, the one or more in organic base and inorganic base, organic base Such as TEA (triethylamine), DIPEA (DIPEA), pyridine, imidazoles, the DBU (carbon -7- of 1,8- diazabicylo 11 Alkene) and diethylamine etc.；Inorganic base such as bicarbonate, carbonate, phosphate, hydrophosphate, dihydric phosphate, sodium hydroxide, Potassium hydroxide, lithium hydroxide and cesium hydroxide etc..As preferred embodiment, described alkali is selected from sodium acid carbonate, carbonic acid Hydrogen potassium, TEA or DIPEA.The equivalent of alkali is 0.5-10 in acylation reaction system；More preferably the equivalent of alkali is 1-3.
Wherein, the acylation reaction of step (1) is carried out in solvent 1, and described solvent 1 is selected from THF (tetrahydrofuran), DCM (dichloromethane), DCE (adjacent dichloroethanes), one or several kinds are arbitrarily to compare in the non-protonic solvent such as ethyl acetate and water Example combination；Preferably, described solvent 1 is selected from THF, acetone or DCM.Further, the volume of solvent 1 and compound A mass Than for 3-100mL/g；It is highly preferred that the volume of solvent 1 and compound A mass ratioes are 10-30mL/g.
Wherein, the acylation reaction temperature of step (1) is -40 DEG C -40 DEG C (subzero 40 DEG C to 40 DEG C), is incubated 2-5h；It is more excellent - 20 DEG C -15 DEG C of choosing, it is incubated 3h.
In the method for the present invention, also containing step (2)：Elimination reaction, specifically：Intermediate B under inert gas shielding, Elimination reaction occurs in the basic conditions to obtain replacing Buddhist nun according to Shandong；
Wherein, in step (2), described alkali is also not particularly limited, one or more of in organic base and inorganic base With, organic base such as TEA, DIPEA, pyridine, imidazoles, DBU and diethylamine etc.；Inorganic base such as bicarbonate, carbonate, phosphoric acid Salt, hydrophosphate, dihydric phosphate, sodium hydroxide, potassium hydroxide, lithium hydroxide and cesium hydroxide etc..As preferable reality Mode is applied, described alkali is selected from TEA or DIPEA.Equivalent of the equivalent of alkali in elimination reaction system is between 1-20；More preferably The equivalent of alkali is 2-10.
Wherein, in step (2), elimination reaction is carried out in solvent 2, and described solvent 2 is selected from acetonitrile, ethyl acetate, DMF (dimethylformamide), DME (glycol dimethyl ether), DMSO (dimethyl sulfoxide (DMSO)), NMP (1-METHYLPYRROLIDONE), DCE are (adjacent Dichloroethanes), DMAc (dimethyl acetamide), THF (tetrahydrofuran), toluene, dioxane, one in C1-C4 alcohol and water Kind is any several with the combination of arbitrary ratio；Wherein, C1-C4 alcohol is selected from methanol, ethanol, propyl alcohol, butanol etc.；As excellent The embodiment of choosing, solvent is selected from acetonitrile, acetone or DMF in step (2).Further, the volume of solvent 2 is with compound B's Mass ratio is 3-100mL/g；It is highly preferred that the volume of solvent 2 and compound B mass ratio 10-30mL/g.
Wherein, the reaction temperature of the elimination reaction of step (2) is 20 DEG C -100 DEG C, is incubated 5-25h；More preferably 60 DEG C -90 DEG C, it is incubated 6-24h.
In the present invention, step (1) and step (2) are reacted under the protection of inert gas, as preferable reality Mode is applied, described inert gas is selected from nitrogen or argon gas.
On the other hand, present invention also offers a kind of compound as shown in formula B：
Wherein R is halogen, sulfonate ester group, bound phosphate groups or sulfate group；As exemplary example, as Cl, Br, I, F, OTs, OTf or OMs；In the preferred embodiment of the invention, described R is Cl or Br.
On the other hand, present invention also offers the compound described in formula B to prepare treatment according to Shandong for Buddhist nun or derivatives thereof side The purposes in face.
The present invention according to Shandong for Buddhist nun preparation method raw material be easy to get, concise in technology, environmental protection and economy and be adapted to industrialized production, What it was prepared replaces impurity in Buddhist nun few according to Shandong, high income.
Brief description of the drawings
Fig. 1 is the preparation technology route map that Buddhist nun is replaced according to Shandong of the present invention；
Fig. 2 be embodiment 1 be prepared (R) -1- (3- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3, 4-d] 1 piperidin-1-yl of pyrimidine -1- bases) -3- chloropropyl -1- ketone nucleus magnetic hydrogen spectrum figure；
Fig. 3 is the nucleus magnetic hydrogen spectrum figure that Buddhist nun is replaced according to Shandong that embodiment 1 is prepared.
Embodiment
Term " equivalent of alkali " is equal to the molal weight (mole) of molal weight (mole)/principal goods material (A or B) of alkali Ratio.Specifically, in step (1), refer to the ratio of the molal weight (mole) of alkali and material A；In step (2), refer to alkali with The ratio of material B molal weight (mole).
Acylation reaction refers to the reaction that hydrogen or other groups are substituted by acyl group.
Elimination reaction refers to slough reaction or elimination reaction, refers to an organic compound molecule and other substance reactions, Lose the organic reaction of part atom or functional group's (being referred to as leaving group).
Embodiment 1
Process route such as following formula:
(1)：Acylation reaction：Intermediate compound B：(R) -1- (3- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos The piperidin-1-yl of [3,4-d] pyrimidine -1- bases 1) -3- chloropropyl -1- ketone synthesis:
250ml THF, 20g compound A, 10g sodium acid carbonates (2.3eq) are added in reaction bulb, be cooled under nitrogen protection- 20 DEG C, 7.2g 3- chlorpromazine chlorides (1.05eq) and 50mlTHF mixed liquors is added dropwise, drop finishes, and insulation 3h to raw material reaction is finished.Return Washed to 15~25 DEG C of room temperature, filtering, 200ml EA elution filter cakes, mother liquor after merging with 150ml 1% aqueous hydrochloric acid solution, then 150ml saturated sodium-chlorides, saturated sodium bicarbonate are used respectively, and saturated sodium-chloride washs three times, obtains the faint yellow organic phase in upper strata.Temperature control T≤40 DEG C, organic phase is concentrated under reduced pressure, dries, obtain off-white powder compound B 23.5g, yield 99%.1H-NMR (400Mz, CDCl3) δ：8.36~8.39 (d, J=13.2Hz, 1H), 7.64~7.66 (m, 2H), 7.39~7.41 (m, 2H), 7.09~7.18 (m, 5H), 5.72 (br, 2H), 4.85~4.89 (m, 1.5H), 4.53-4.56 (m, 0.5H), 4.04~4.06 (m, 0.5H), 3.72~3.87 (m, 3H), 3.35 (m, 0.5H), 3.19 (m, 0.5H), 2.78~2.90 (m, 2H), 2.27~ 2.43 (m, 2H), 1.96~2.05 (m, 1H), 1.72~1.676 (m, 1H) (Fig. 2).
(2) elimination reaction：The preparation of Buddhist nun is replaced according to Shandong:
By compound (R) -1- (3- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases 1 Piperidin-1-yl) -3- chloropropyl -1- ketone solids 23.5g addition 200ml acetonitriles, 32g triethylamines (6.0eq), risen under nitrogen protection To 70~75 DEG C, 6~10h of insulation to raw material reacts to not having substantially temperature, is down to 30 DEG C and is concentrated under reduced pressure into after T≤40 DEG C without evaporating Point.100ml methanol is added into the system after concentration to whole dissolvings, 40~45 DEG C is warming up to, 100ml purified waters, analysis is added dropwise Go out a large amount of white solids, be cooled to 15~20 DEG C, stirring 2h filter white solid replaces Buddhist nun 13.77g, two step total recoverys according to Shandong 80.5%, purity 99.56%.1H-NMR (400Mz, DMSO-d6)δ：8.23 (s, 1H), 7.65~7.67 (m, 2H), 7.40~ 7.44 (m, 2H), 7.11~7.19 (m, 5H), 6.67~6.74 (m, 1H), 6.04~6.15 (m, 1H), 5.57~5.71 (m, 1H), 4.69~4.72 (m, 1H), 4.55~4.56 (m, 0.5H), 4.20~4.22 (m, 1H), 4.05~4.08 (m, 0.5H), 3.70~3.73 (m, 0.5H), 3.15~3.21 (m, 1H), 3.00 (m, 0.5H), 2.24~2.30 (m, 1H), 2.08~2.13 (m, 1H), 1.90~1.93 (m, 1H), 1.58~1.60 (m, 1H) (Fig. 3).
Embodiment 2
(1) acylation reaction：250ml THF, 20g compound A, 10g sodium acid carbonates (2.3eq), nitrogen are added in reaction bulb - 10 DEG C are cooled under protection, 7.2g 3- chlorpromazine chlorides (1.05eq) and 50mlTHF mixed liquors is added dropwise, drop finishes, insulation 3h to original Material reaction finishes.15~25 DEG C of room temperature is back to, is filtered, 200ml EA elution filter cakes, mother liquor uses 150ml 1% salt after merging Aqueous acid washs, then uses 150ml saturated sodium-chlorides respectively, saturated sodium bicarbonate, and saturated sodium-chloride washs three times, and it is light to obtain upper strata Yellow organic phase.Temperature control T≤40 DEG C, organic phase is concentrated under reduced pressure, and is dried, is obtained off-white powder compound B 23.5g, yield 99%.1H-NMR (400Mz, CDCl3)δ：8.36~8.39 (d, J=13.2Hz, 1H), 7.64~7.66 (m, 2H), 7.39~ 7.41 (m, 2H), 7.09~7.18 (m, 5H), 5.72 (br, 2H), 4.85~4.89 (m, 1.5H), 4.53-4.56 (m, 0.5H), 4.04~4.06 (m, 0.5H), 3.72~3.87 (m, 3H), 3.35 (m, 0.5H), 3.19 (m, 0.5H), 2.78~2.90 (m, 2H), 2.27~2.43 (m, 2H), 1.96~2.05 (m, 1H), 1.68~1.72 (m, 1H).
(2) elimination reaction：By compound (the R) -1- prepared in embodiment 2 (3- (4- amino -3- (4- Phenoxyphenyls) - The piperidin-1-yl of 1H- pyrazolos [3,4-d] pyrimidine -1- bases 1) -3- chloropropyl -1- ketone solids 23.5g addition 300ml acetonitriles, DIPEA (6.0eq), 70~85 DEG C are warming up under argon gas protection, 6~10h of insulation to raw material is reacted to not having substantially, is down to 30 DEG C it is concentrated under reduced pressure into no cut after T≤40 DEG C.100ml methanol is added into the system after concentration to whole dissolvings, is warming up to 40~45 DEG C, 100ml purified waters are added dropwise, separate out a large amount of white solids, be cooled to 15~20 DEG C, stirring 2h filters to obtain white solid Buddhist nun 13.5g is replaced according to Shandong, two step total recoverys are 78.9%, purity 99.24%；1H-NMR (400Mz, DMSO-d6)δ：8.23 (s, 1H), 7.65~7.67 (m, 2H), 7.40~7.44 (m, 2H), 7.11~7.19 (m, 5H), 6.67~6.74 (m, 1H), 6.04~6.15 (m, 1H), 5.57~5.71 (m, 1H), 4.69~4.72 (m, 1H), 4.55~4.56 (m, 0.5H), 4.20~ 4.22 (m, 1H), 4.05~4.08 (m, 0.5H), 3.70~3.73 (m, 0.5H), 3.15~3.21 (m, 1H), 3.00 (m, 0.5H), 2.24~2.30 (m, 1H), 2.08~2.13 (m, 1H), 1.90~1.93 (m, 1H), 1.58~1.60 (m, 1H).
Embodiment 3
(1) acylation reaction：(R) -1- (3- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine - The piperidin-1-yl of 1- bases 1) -3- chloropropyl -1- ketone synthesis
152ml THF, 7.6g compound A, 3.1g DIPEA (1.2eq) are added in reaction bulb, be cooled under nitrogen protection- 15 DEG C, 2.9g 3- chlorpromazine chlorides (1.13eq) and 15mlTHF mixed liquors is added dropwise, drop finishes, and insulation 3h to raw material reaction is finished.Return To 15~25 DEG C of room temperature, filtering, 76ml EA elution filter cakes, mother liquor is washed after merging with 60ml 1% aqueous hydrochloric acid solution, then is divided Not Yong 60ml saturated sodium-chlorides, saturated sodium bicarbonate, saturated sodium-chloride wash three times, obtain the faint yellow organic phase in upper strata.Temperature control T≤ 40 DEG C, organic phase is concentrated under reduced pressure dry, obtains off-white powder compound B 10.5g, yield 99%.
(2) elimination reaction：By compound (R) -1- (3- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4- D] 1 piperidin-1-yl of pyrimidine -1- bases) -3- chloropropyl -1- ketone solids 10.5g adds 76ml acetonitriles, 12.2g triethylamines (6.0eq), 50~55 DEG C are warming up under nitrogen protection, also have a small amount of starting material left after being incubated 24h, be down to 30 DEG C after T≤40 DEG C it is concentrated under reduced pressure into no cut.40ml methanol is added into the system after concentration to whole dissolvings, is warming up to 40~45 DEG C, drop Add 40ml purified waters, separate out a large amount of white solids, be cooled to 15~20 DEG C, stirring 2h filter white solid replaces Buddhist nun according to Shandong 4.7g, two step total recoverys 72.3%, purity 97.58%.1H-NMR (400Mz, DMSO-d6)δ：8.23 (s, 1H), 7.65~7.67 (m, 2H), 7.40~7.44 (m, 2H), 7.11~7.19 (m, 5H), 6.67~6.74 (m, 1H), 6.04~6.15 (m, 1H), 5.57~5.71 (m, 1H), 4.69~4.72 (m, 1H), 4.55~4.56 (m, 0.5H), 4.20~-4.22 (m, 1H), 4.05 ~4.08 (m, 0.5H), 3.70~3.73 (m, 0.5H), 3.15~3.21 (m, 1H), 3.00 (m, 0.5H), 2.24~2.30 (m, 1H), 2.08~2.13 (m, 1H), 1.90~1.93 (m, 1H), 1.58~1.60 (m, 1H).
Embodiment 4
(1) acylation reaction：(R) -1- (3- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine - The piperidin-1-yl of 1- bases 1) -3- chloropropyl -1- ketone synthesis
300ml acetone is added in reaction bulb, 20g compounds A, 8.7g sodium acid carbonate (2.0eq), nitrogen protection is lower to cool To -20 DEG C, 7.8g 3- chlorpromazine chlorides (1.17eq) and 50ml acetone mixtures is added dropwise, drop finishes, and insulation 3h to raw material has reacted Finish.15~25 DEG C of room temperature is back to, is filtered, 200ml EA elution filter cakes, mother liquor is washed after merging with 200ml 1% aqueous hydrochloric acid solution Wash, then use 200ml saturated sodium-chlorides respectively, saturated sodium bicarbonate, saturated sodium-chloride washs three times, and it is faint yellow organic to obtain upper strata Phase.Temperature control T≤40 DEG C, organic phase is concentrated under reduced pressure dry, obtains off-white powder compound B 25.4g, yield 99%.
(2) elimination reaction：By compound (R) -1- (3- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4- D] 1 piperidin-1-yl of pyrimidine -1- bases) -3- chloropropyl -1- ketone solids 25.4g adds 200ml acetonitriles, 32g triethylamines (6.0eq), 70~75 DEG C are warming up under nitrogen protection, is incubated after 17h substantially without starting material left, is down to 30 DEG C and is concentrated under reduced pressure after T≤40 DEG C To without cut.100ml methanol is added into the system after concentration to whole dissolvings, 40~45 DEG C is warming up to, it is pure that 100ml is added dropwise Change water, separate out a large amount of white solids, be cooled to 15~20 DEG C, stirring 2h filter white solid replaces Buddhist nun 13.9g according to Shandong, two steps are total Yield 61%, purity 96.87%.1H-NMR (400Mz, DMSO-d6)δ：8.23 (s, 1H), 7.65~7.67 (m, 2H), 7.40~ 7.44 (m, 2H), 7.11~7.19 (m, 5H), 6.67~6.74 (m, 1H), 6.04~6.15 (m, 1H), 5.57~5.71 (m, 1H), 4.69~4.72 (m, 1H), 4.55~4.56 (m, 0.5H), 4.20~-4.22 (m, 1H), 4.05~4.08 (m, 0.5H), 3.70~3.73 (m, 0.5H), 3.15~3.21 (m, 1H), 3.00 (m, 0.5H), 2.24~2.30 (m, 1H), 2.08 ~2.13 (m, 1H), 1.90~1.93 (m, 1H), 1.58~1.60 (m, 1H).
Embodiment 5
(1) acylation reaction：(R) -1- (3- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine - The piperidin-1-yl of 1- bases 1) -3- bromopropyl -1- ketone synthesis
300ml dichloromethane (DCM), 20g compounds A, 8.2g pyridine (2.0eq), under nitrogen protection are added in reaction bulb - 20 DEG C are cooled to, 4.0g3- bromopropionyl bromides (1.15eq) and 50mlTHF mixed liquors is added dropwise, drop finishes, and insulation 3h to raw material has reacted Finish.15~25 DEG C of room temperature is back to, is filtered, 200ml EA elution filter cakes, mother liquor is washed after merging with 200ml 1% aqueous hydrochloric acid solution Wash, then use 200ml saturated sodium-chlorides respectively, saturated sodium bicarbonate, saturated sodium-chloride washs three times, and it is faint yellow organic to obtain upper strata Phase.Temperature control T≤40 DEG C, organic phase is concentrated under reduced pressure dry, obtains off-white powder compound B 15.5g, yield 99%.
(2) elimination reaction：By compound (R) -1- (3- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4- D] 1 piperidin-1-yl of pyrimidine -1- bases) -3- bromopropyl -1- ketone solids 15.5g adds 200ml acetonitriles, 32g triethylamines (6.0eq), 70~75 DEG C are warming up under nitrogen protection, is incubated after 14h substantially without starting material left, is down to 30 DEG C and is concentrated under reduced pressure after T≤40 DEG C To without cut.100ml methanol is added into the system after concentration to whole dissolvings, 40~45 DEG C is warming up to, it is pure that 100ml is added dropwise Change water, separate out a large amount of white solids, be cooled to 15~20 DEG C, stirring 2h filter faint yellow solid replaces Buddhist nun 9.7g, two steps according to Shandong Total recovery 42.5%, purity 91.32%.1H-NMR (400Mz, DMSO-d6)δ：8.23 (s, 1H), 7.65~7.67 (m, 2H), 7.40~7.44 (m, 2H), 7.11~7.19 (m, 5H), 6.67~6.74 (m, 1H), 6.04~6.15 (m, 1H), 5.57~ 5.71 (m, 1H), 4.69~4.72 (m, 1H), 4.55~4.56 (m, 0.5H), 4.20~-4.22 (m, 1H), 4.05~4.08 (m, 0.5H), 3.70~3.73 (m, 0.5H), 3.15~3.21 (m, 1H), 3.00 (m, 0.5H), 2.24~2.30 (m, 1H), 2.08~2.13 (m, 1H), 1.90~1.93 (m, 1H), 1.58~1.60 (m, 1H).
Embodiment 6
(1) acylation reaction：6 (R) -1- (3- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine - The piperidin-1-yl of 1- bases 1) -3- chloropropyl -1- ketone synthesis
1500ml THF, 100g compound A, 50g sodium acid carbonates (2.3eq) are added in reaction bulb, nitrogen protection is lower to cool To -20 DEG C, 36.0g 3- chlorpromazine chlorides (1.1eq) and 200mlTHF mixed liquors is added dropwise, drop finishes, and insulation 3h to raw material has reacted Finish.15~25 DEG C of room temperature is back to, is filtered, 1000ml EA elution filter cakes, mother liquor uses 1000ml 1% aqueous hydrochloric acid solution after merging Washing, then use 1000ml saturated sodium-chlorides respectively, saturated sodium bicarbonate, and saturated sodium-chloride washing three times, obtains that upper strata is faint yellow to be had Machine phase.Temperature control T≤40 DEG C, organic phase is concentrated under reduced pressure dry, obtains off-white powder compound B 128g, yield 99%.
(2) elimination reaction：The preparation of Buddhist nun is replaced according to Shandong：
Compound B solids 128g is added into 1230ml acetonitriles, 156.6g triethylamines (6.0eq), is warming up under nitrogen protection 70~75 DEG C, 6~10h of insulation to raw material is reacted to not having substantially, is down to 30 DEG C and is concentrated under reduced pressure into no cut after T≤40 DEG C. 1000ml methanol is added into the system after concentration to whole dissolvings, 40~45 DEG C is warming up to, 1000ml purified waters is added dropwise, separate out A large amount of white solids, are cooled to 15~20 DEG C, stirring 2h filter white solid replaces Buddhist nun 85.5g, two step total recoverys according to Shandong 75%, purity 99.86%.1H-NMR (400Mz, DMSO-d6)δ：8.23 (s, 1H), 7.65~7.67 (m, 2H), 7.40~ 7.44 (m, 2H), 7.11~7.19 (m, 5H), 6.67~6.74 (m, 1H), 6.04~6.15 (m, 1H), 5.57~5.71 (m, 1H), 4.69~4.72 (m, 1H), 4.55~4.56 (m, 0.5H), 4.20~-4.22 (m, 1H), 4.05~4.08 (m, 0.5H), 3.70~3.73 (m, 0.5H), 3.15~3.21 (m, 1H), 3.00 (m, 0.5H), 2.24~2.30 (m, 1H), 2.08 ~2.13 (m, 1H), 1.90~1.93 (m, 1H), 1.58~1.60 (m, 1H).

Claims (10)

1. a kind of preparation method that Buddhist nun is replaced according to Shandong, is comprised the steps of：
(1) acylation reaction：Acylation reaction occurs in solvent 1 and obtains intermediate B by compound A and compound C；
(2) elimination reaction：Elimination reaction occurs in solvent 2 and obtains replacing Buddhist nun according to Shandong for intermediate B；
Wherein, R, X are separately to be selected from leaving function.
2. according to the method for claim 1, it is characterised in that described R, X is separately selected from halogen, sulfonate group Group, bound phosphate groups or sulfate group；It is highly preferred that described R, X separately selected from Cl, Br, I, F, OTs, OTf or OMs；It is highly preferred that described R, X are separately selected from Cl or Br.
3. according to the method for claim 1, it is characterised in that
In step (1), described solvent 1 is selected from THF, DCM, DCE, the one or more in ethyl acetate and water；Preferably, institute The solvent 1 stated is selected from THF, acetone or DCM；
Preferably, in step (1), the volume of solvent 1 and compound A mass ratio are 3-100mL/g；It is highly preferred that solvent 1 Volume and compound A mass ratio are 10-30mL/g；
Preferably, in step (1), compound A and compound C molar ratio is 4:1-1:5；More preferably 0.8:1-1:0.8.
4. according to the method for claim 1, it is characterised in that the acylation reaction of step (1) is entered in the presence of a base OK, one or more of the described alkali in organic base or inorganic base；
Preferably, described organic base is selected from TEA, DIPEA, pyridine, imidazoles, the one or more in DBU and diethylamine；
Preferably, described inorganic base is selected from bicarbonate, carbonate, phosphate, hydrophosphate, dihydric phosphate, hydroxide Sodium, potassium hydroxide, the one or more in lithium hydroxide and cesium hydroxide；
Preferably, described alkali is selected from sodium acid carbonate, saleratus, TEA or DIPEA；
Preferably, in acylation reaction system, the equivalent of alkali is 0.5-10；More preferably the equivalent of alkali is 1-3.
5. according to the method for claim 1, it is characterised in that step (1) acylation reaction temperature is -40 DEG C -40 DEG C, insulation 2-5h；It is preferred that -20 DEG C -15 DEG C, it is incubated 3h.
6. according to the method for claim 1, it is characterised in that
Step (2), described solvent 2 are selected from acetonitrile, ethyl acetate, DMF, DME, DMSO, NMP, DCE, DMAc, THF, toluene, Dioxane, one or any several combination in C1-C4 alcohol and water；
Preferably, C1-C4 alcohol is selected from methanol, ethanol, propyl alcohol, butanol；
Preferably, in step (2), described solvent 2 is selected from acetonitrile, acetone or DMF.
Preferably, in step (2), the volume of solvent 2 and compound B mass ratio are 3-100mL/g；It is highly preferred that solvent 2 Volume and compound B mass ratio 10-30mL/g.
7. according to the method for claim 1, it is characterised in that the elimination reaction of step (2) is entered in the environment of alkali presence Row reaction, one or more of the described alkali in organic base or inorganic base；
Preferably, described organic base is selected from TEA, DIPEA, pyridine, imidazoles, the one or more in DBU and diethylamine；
Preferably, described inorganic base is selected from bicarbonate, carbonate, phosphate, hydrophosphate, dihydric phosphate, hydroxide Sodium, potassium hydroxide, the one or more in lithium hydroxide and cesium hydroxide；
Preferably, described alkali is selected from TEA or DIPEA；
Preferably, in elimination reaction system, the equivalent of alkali is 1-20；More preferably the equivalent of alkali is 2-10.
Preferably, in step (2), elimination reaction temperature is 20 DEG C -100 DEG C, is incubated 5-25h；More preferably 60 DEG C -90 DEG C, insulation 6-24h。
8. according to the method for claim 1, it is characterised in that described step (1) acylation reaction and step (2) eliminate instead It should be reacted under the protection of inert gas；Preferably, described inert gas is nitrogen or argon gas.
9. compound or its pharmaceutically acceptable salt and solvate shown in formula B,
Wherein, R is halogen, sulfonate ester group, bound phosphate groups or sulfate group；Preferably, described R be Cl, Br, I, F, OTs, OTf or OMs；It is highly preferred that R is Cl or Br.
10. the compound described in claim 9 is preparing the purposes according to Shandong for Buddhist nun or derivatives thereof aspect.
CN201711024520.6A 2017-10-27 2017-10-27 The preparation method of Buddhist nun is replaced according to Shandong Withdrawn CN107814804A (en)

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CN112851527A (en) * 2020-12-31 2021-05-28 湖北英纳氏生物科技有限公司 Preparation method of m-aminophenylacetylene
CN113929686A (en) * 2020-06-29 2022-01-14 鲁南制药集团股份有限公司 Preparation method of ibrutinib
CN115073475A (en) * 2022-07-02 2022-09-20 浙江美诺华药物化学有限公司 Synthetic method of ibrutinib

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CN107108640A (en) * 2015-01-14 2017-08-29 药品循环有限责任公司 The synthesis of bruton's tyrosine kinase inhibitor

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CN105859721A (en) * 2015-01-22 2016-08-17 浙江京新药业股份有限公司 Method for preparing 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

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CN113929686A (en) * 2020-06-29 2022-01-14 鲁南制药集团股份有限公司 Preparation method of ibrutinib
CN113929686B (en) * 2020-06-29 2023-08-22 鲁南制药集团股份有限公司 Preparation method of ibutenib
CN112851527A (en) * 2020-12-31 2021-05-28 湖北英纳氏生物科技有限公司 Preparation method of m-aminophenylacetylene
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CN115073475A (en) * 2022-07-02 2022-09-20 浙江美诺华药物化学有限公司 Synthetic method of ibrutinib

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